Open Access

Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)

  • Authors:
    • Xiaoran Ma
    • Jibiao Wu
    • Bin Wang
    • Cun Liu
    • Lijuan Liu
    • Changgang Sun
  • View Affiliations

  • Published online on: September 20, 2022     https://doi.org/10.3892/ijo.2022.5424
  • Article Number: 134
  • Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD‑1)/programmed death ligand 1 (PD‑L1) axis have achieved marked and durable efficacy in patients with different solid tumors and have improved their survival. However, the presence of primary or acquired resistance to immune checkpoint blockades results in only a small fraction of patients benefiting from the treatment. An increasing number of preclinical studies have reported that PD‑L1 expression in tumor cells is involved in a number of epigenetic changes, including histone modifications, non‑coding RNA regulation and DNA methylation. In addition, multiple epigenetic targeting drugs have been demonstrated to directly or indirectly interfere with PD‑L1 expression in various cancer models. This provides opportunities to better characterize the regulatory mechanisms of PD‑L1 expression and explore novel therapeutic strategies to improve immunosuppressant response rates and overcome drug resistance. The present review focuses on the latest findings and evidence on the epigenetic mechanism regulating PD‑L1 expression and discusses the biological and clinical implications of this regulatory mechanism in solid tumors. A rational combination of epigenetic regulation and PD‑1/PD‑L1 axis blockade may improve the prognosis of patients with solid tumors.

1. Introduction

Programmed death ligand 1 (PD-L1) is a type I transmembrane protein encoded by the CD274 gene (1,2). Immunohistochemical detection has revealed that PD-L1 mRNA and protein expression is upregulated in various cancer types (3). However, since PD-L1 mRNA is strictly post-transcriptionally regulated under normal physiological conditions, PD-L1 protein is scarcely expressed in normal cells (4). As a key member of the immune checkpoints, PD-L1, together with its receptor programmed cell death protein 1 (PD-1), serves an important role in tumor cell clearance and immune surveillance by mediating signaling processes that limit autoimmunity and prevent excessive immune responses (5). In addition, quantification of PD-L1 expression by immunohistochemistry on different detection platforms has been used in various clinical trials as a key determinant of the efficacy of checkpoint immunotherapy (6).

As one of the most promising approaches to activate the immune system, immune checkpoint blockade has achieved remarkable efficacy in antitumor therapy in the last decade (7). In addition, the exploration of drugs targeting the PD-1/PD-L1 axis has led to the development of a number of immune checkpoint inhibitors (ICIs), such as anti-PD-L1 monoclonal antibodies (atezolizumab, durvalumab and avelumab) and anti-PD-1 monoclonal antibodies (nivolumab, pembrolizumab and tislelizumab), which have become first-line therapy for various solid tumors (3,8,9). These ICIs enhance the immune system surveillance capacity and generate antitumor immune responses by manipulating the interaction between PD-L1 and PD-1, leading to improved overall survival (OS) and progression-free survival (PFS) of patients with cancer (3,10).

However, due to the diversity and complexity of the tumor immune microenvironment and the continuous genetic changes in tumor cells, immunotherapy is ineffective in most patients with advanced tumors (11,12). In addition, the complex drug resistance mechanism of cancer cells to immunotherapy influences the clinical outcomes of patients with cancer (13). Therefore, a combination therapy to improve the response rate to PD-1/PD-L1 blockade and overcome resistance to anti-PD-1/PD-L1 therapy is urgently required. Epigenetic modifications that serve an important role in interactions between the tumor microenvironment and tumor cells and in the development of cancer cells represent such opportunities (14).

Epigenetic modifications are heritable changes in gene expression caused by environmental, dietary, age and disease factors that do not include changes in the DNA sequence itself (15). Epigenetic modifications can reshape the tumor microenvironment and alter cellular phenotypes through aberrant histone patterns, non-coding RNAs levels and DNA methylation at specific promoters, enabling cells to grow and evade immune surveillance (16). Since epigenetic modifications are susceptible to external factors and are often reversible, they are considered to be potential therapeutic targets for various cancer types (17). Azacitidine, the first epigenetic drug approved by the Food and Drug Administration (FDA), marks a breakthrough in epigenetic medicine from theory to application (18). Tazemetostat, a small-molecule inhibitor of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), has recently been approved by the FDA to treat solid tumors, including relapsed or refractory follicular lymphoma and locally advanced or metastatic epithelioid sarcoma (19). In addition, multiple DNA methyltransferase (DNMT) inhibitors and histone-modifying enzyme inhibitors have shown promising therapeutic effects in solid tumors highlighting the potential of epigenetic therapy in the treatment of solid tumors (20,21).

Detailed descriptions of the resistance mechanisms of ICIs targeting the PD-1/PD-L1 axis have been provided in several studies (22,23); therefore, these are only briefly summarized in the present review. In addition, the latest research progress and related mechanisms of epigenetic factors interfering with PD-L1 expression, including histone modifications such as acetylation and methylation, non-coding RNA regulation and DNA methylation, in solid tumors are summarized and discussed (Fig. 1). Among them (Table I), a variety of chromatin-modifying enzymes can regulate PD-L1 expression by affecting the modifications that occur on lysine and arginine residues (24-26). Noncoding RNAs can inhibit PD-L1 expression by binding to the 3′ UTR or act as upstream regulators of the PD-1/PD-L1 axis (27-29). The research on DNA methylation mainly focuses on its effect on the PD-L1 promoter (30). The present review aims to provide novel insights for further development of potential combination therapy strategies to improve the response rate and tolerability of immunotherapy in solid tumors.

Table I

Epigenetic modifications of PD-L1 in solid tumors.

Table I

Epigenetic modifications of PD-L1 in solid tumors.

A, Histone acetylation
First author/s, yearTumor typesKey findings(Refs.)
Wang et al, 2020Breast cancerHDAC3 could maintain PD-L1 expression by inhibiting histone H3 acetylation at the PD-L1 promoter(12)
Shen et al, 2021HDAC1/2 could be recruited by TET2 proteins to the PD-L1 promoter to deacetylate H3K27ac and thereby inhibit the transcription of PD-L1(24)
Xu et al, 2021HDAC2 could affect IFNγ-induced PD-L1 expression by activating the JAK-STAT1 pathway(64)
Darvin et al, 2019HDAC1 and HAT affected EMT-induced upregulation of PD-L1 expression(65)
Wang et al, 2020Lung cancerHDAC3 could maintain PD-L1 expression by inhibiting histone H3 acetylation at the PD-L1 promoter(12)
Liu et al, 2020HDAC10 was positively associated with PD-L1 expression(63)
Shin et al, 2022PD-L1 protein expression levels were dose-dependently decreased by Nexturastat A(79)
Briere et al, 2018Mocetinostat upregulated PD-L1(71)
Wang et al, 2020Hepatocellular carcinomaHDAC3 could maintain PD-L1 expression by inhibiting histone H3 acetylation at the PD-L1 promoter(12)
Mondello et al, 2020LymphomasHDAC3 inhibition led to the upregulation of PD-L1 expression(56)
Huang et al, 2018Class I-selective HDACis upregulated PD-L1 expression(74)
Deng et al, 2019HDAC3 inhibitors could rapidly increase recruitment of bromodomain protein BRD4 at the promoter region of the PD-L1 gene, leading to activation of its transcription(55)
Wang et al, 2018Pancreatic cancerHDAC3 regulated PD-L1 expression by intervening in the STAT3 signaling pathway(59)
Fan et al, 2019Upregulation of HAT1 expression is not only associated with poor prognosis but can also enhance PD-L1 transcription by promoting the binding of BRD4-containing complex to acetylated histone H4(25)
Hu et al, 2019MelanomasHDAC8 participated in the transcriptional activation of PD-L1 by acting on STAT3 containing transcriptional complexes(58)
M et al, 2016HDAC6 controlled PD-L1 expression by affecting the recruitment and activation of STAT3(60)
Woods et al, 2015Class I HDACis upregulated PD-L1 expression(75)
Keremu et al, 2019OsteosarcomaTranscription factor STAT3 mediated the regulation of PD-L1 expression by HDAC6(61)
Que et al, 2021ChondrosarcomaChidamide upregulated PD-L1 expression by activating the transcription factor STAT1(72)
Sheikh et al, 2021Class I HDACis elevated PD-L1 expression(73)
Liu et al, 2020Prostate cancerSAHA increased the histone H3 acetylation of the CD274 promoter to induce CD274 transcription, which led to the upregulation of PD-L1 expression(76)
Shi et al, 2021Colorectal cancerRomidepsin increased PD-L1 expression through regulation of histone acetylation(52)
Chen et al, 2019MPT0G612 downregulated PD-L1 expression induced by IFN-γ(78)
Kuroki H, 2021Urothelial cancerInhibition of HDAC6 resulted in decreased expression levels of PD-L1(80)

B, Histone methylation
Sasidharan Nair et al, 2020Colorectal cancerTranscriptional upregulation of PD-L1 was positively associated with H3K4me3 and negatively associated with H3K9me3(84)
Liu et al, 2021Silencing of KDM4B reduced PD-L1 expression by promoting H3K27me3 expression and decreasing HOXC4 expression(90)
Liu et al, 2021IOX1 downregulated PD-L1 expression in a concentration-dependent manner(93)
Darvin et al, 2019Breast cancerInhibitory histones H3K9me3 and H3K27me3 regulated PD-L1 expression(65)
Qin et al, 2019HCI-2509 upregulated PD-L1 expression in a dose-dependent manner(92)
Liu et al, 2021IOX1 downregulated PD-L1 expression in a concentration-dependent manner(93)
Jiang et al, 2021Cervical cancerPRMT5 promoted the transcription of STAT1, and thus, PD-L1 expression via symmetric dimethylation of histone H3R2(86)
Lu et al, 2017Pancreatic cancerMLL1 catalyzed H3K4me3 to activate the transcription of PD-L1 by directly binding to the CD274 promoter(26)
Zhou et al, 2021Prostate cancerKnockdown of WDR5 reduced IFN-γ-induced PD-L1 mRNA and protein levels(87)
Zingg et al, 2017MelanomaInactivation of EZH2 led to decreased PD-L1 mRNA levels(53)
Zhao et al, 2019Lung cancerEZH2 was positively associated with PD-L1 levels and regulated PD-L1 expression through HIF-1α(89)
Soldi et al, 2020Ovarian cancerSP-2577 promoted PD-L1 expression by inhibiting LSD1(91)

C, Histone phosphorylation
Wang et al, 2021Hepatocellular carcinomaEGF phosphorylated histone H3 at thr11, which induced PD-L1 expression(30)

D, miRNA
Tang et al, 2018Lung cancermiR-3127-5p induced PD-L1 expression by promoting p-STAT3(107)
Xia et al, 2021Inhibition of miR-377-3p and miR-155-5p expression directly led to upregulated PD-L1 levels(27)
Hong et al, 2020; Zhang et al, 2021Overexpressed let-7 miRNA inhibited the mRNA levels of PD-L1(109, 110)
Xie et al, 2018Overexpression of miR-140 suppressed PD-L1 expression by directly binding to its 3′ UTR(111)
Katakura et al, 2020miR-200b regulated PD-L1 expression and was negatively associated with PD-L1 expression(113)
Anastasiadou et al, 2021Ovarian cancermiR-200c decreased PD-L1 expression(114)
Rogers et al, 2019Breast cancermiR-200c inhibited PD-L1 upregulation(115)
Dou et al, 2020miR-92 could upregulate PD-L1 expression by promoting YAP1 phosphorylation(118)
Zhang et al, 2020miR-5119 improved antitumor immunotherapy efficacy possibly by downregulating PD-L1 expression(119)
Wang et al, 2020miR-570-3p inhibited proliferation, invasion and migration, and induced apoptosis by targeting CD274(120)
Yang et al, 2018miR-195 and miR-497 modulated CD274 expression by binding to the 3′ UTR(121)
Li et al, 2019miR-3609 bound to the 3′ UTR of PD-L1 to regulate PD-L1 expression(122)
Yao et al, 2020miR-27a-3p could upregulate PD-L1 by activating the PTEN-AKT/PI3K pathway(125)
Li et al, 2019Oral cancermiR-21 downregulated PTEN and thereby increased PD-L1 expression(126)
Li et al, 2020Gastric cancerExosomal miR-16-5p specifically targeted and downregulated PD-L1(127)
Miliotis et al, 2021miR-105-5p suppressed PD-L1 expression by directly targeting important cis-acting regulatory regions in the PD-L1 3′ UTR(128)
Wang et al, 2012Guanine to cytosine mutations at the 3′ UTR region could disrupt miR-570 binding leading to overexpression of PD-L1(129)
Liu et al, 2021Colorectal cancermiR-15a potently repressed HOXC4 transcription by targeting KDM4B in colorectal cancer cells, thereby reducing PD-L1 expression(90)
Ashizawa et al, 2019miR-148a-3p bound to the 3′ UTR region of PD-L1 to reduce the levels of PD-L1(130)
Roshani et al, 2021miR-124 directly targeted a specific region in the PD-L1 3′ UTR to downregulate its expression(131)
Xu et al, 2021HCG18 upregulated PD-L1 by sponging miR-20b-5p(132)
Bian et al, 2021Esophageal cancermiR-493 downregulated PD-L1 expression(136)
Javadrashid et al, 2021Pancreatic cancermiR-612 reduced PD-L1 expression(137)
Cioffi et al, 2017miR-93 and miR-106b can inhibit the expression of PD-L1 at the mRNA and protein levels(138)
Wang and Cao, 2021Hepatocellular carcinomasmiR-329-3p inhibited PD-L1 expression by targeting and downregulating KDM1A(139)
Incorvaia et al, 2020Renal cancermiR-22 and miR-24 were negatively associated with plasma PD-L1 levels(140)

E, lncRNA
Fan et al, 2022Breast cancerlncRNA KRT19P3 reduced PD-L1 expression(148)
Zhang et al, 2020lncRNA GATA3-AS1 could regulate CSN5-mediated PD-L1 deubiquitination(149)
Shang et al, 2019Esophageal cancerlncRNA OIP5-AS1 could trigger CD8+ T cell apoptosis by regulating PD-1/PD-L1(150)
Chen et al, 2021Ovarian cancerlncRNA HOTTIP upregulated PD-L1 expression in neutrophils by promoting the secretion of IL-6(151)
Huang et al, 2022Lung cancerSNHG12 increased the expression stability of PD-L1 through binding of the HuR gene(152)
Shi et al, 2022Oral cancerlncRNA IFITM4P upregulated PD-L1 expression(153)
Wang et al, 2021GliomalncRNA HOTAIR activated the NF-κB pathway to abnormally express PD-L1(154)
Mineo et al, 2020Primary transcript of lncRNA INCR blocks inhibition of the neighboring gene PD-L1 by binding to HNRNPH1(156)
Xu et al, 2019Colorectal cancerlncRNA MIR17HG could increase PD-L1 expression by directly binding PD-L1(157)
Ni et al, 2021When the expression of lncRNA SNHG29 was inhibited, PD-L1 expression was downregulated(147)

F, circRNA
Li et al, 2021Lung cancerhsa_circ_0003222 inhibition reduced anti-PD-L1 resistance in vivo(163)

G, DNA methylation
Lv et al, 2020Gastric cancerPD-L1 promoter methylation was associated with PD-L1 protein expression(167)
Lu et al, 20215-azacytidine increased PD-L1 expression, gemcitabine inhibited PD-L1 expression(169)
Sheikh et al, 2021 ChondrosarcomasDNMT inhibitors induced PD-L1 protein expression(73)
Liu J, 2017Hepatocellular carcinomaHigh DNMT1 expression was positively associated with overexpression of PD-L1 in sorafenib-resistant cells(170)
Wang et al, 2021MEF2D methylation elevated PD-L1 expression(139)
Chatterjee et al, 2018MelanomaDNMT3A was inversely associated with PD-L1 expression, and DNMT inhibitors increased PD-L1 levels(171)
Peng et al, 2015Ovarian cancerDNMT inhibitors augmented the efficacy of PD-L1 blockade therapy(172)
Li et al, 2019Prostate cancerRecombinant plasmids containing the C-terminal domains of both DNMT1 and DNMT3A methyltransferase inhibited PD-L1 expression more potently than DNMT3A alone(173)
Asgarova et al, 2018Non-small cell lung cancerTGFβ1 induced PD-L1 promoter demethylation by reducing the content of DNMT1, which led to PD-L1 expression(175)
Zhang et al, 2017Methylation of the PD-L1 promoter downregulated PD-L1 expression(176)
Lai et al, 2018IFN-γ-related genes IRF-1 and IRF-7 were negatively associated with CD274 expression encoding PD-L1, and decitibine could demethylate IRF-1 and IRF-7, thereby restoring PD-L1 levels(177)
Mu et al, 2018;GliomasHypomethylation of the PD-L1 promoter mediated overexpression of PD-L1(178)
Briand J, et al 2019(179)
Elashi et al, 2018Breast cancerHypomethylation of the PD-L1 promoter mediated overexpression of PD-L1(180)
Jacot et al, 2020BRCA1 promoter hypermethylation was associated with PD-L1 expression(181)
Elashi et al, 2018Colorectal cancerHypomethylation of the PD-L1 promoter mediated overexpression of PD-L1(180)
Yamada et al, 2018PD-L1 expression was more readily observed in microsatellite instability cancer caused by MLH1 promoter methylation(182)
Hua et al, 20215-azacytidine inhibited the downregulation of PD-L1 mRNA and protein levels(183)

[i] 3′ UTR, 3′ untranslated region; ac, acetylation; BRD4, bromodomain containing 4; CSN5, COP9 signalosome subunit 5; DNMT, DNA methyltransferase; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; EZH2, enhancer of zeste homolog 2; HATs, histone acetyltransferases; HCG18, HLA complex group 18; HDACis, HDAC inhibitors; HDACs, histone deacetylases; HIF-1α, hypoxia-inducible factor 1-α; HNRNPH1, heterogeneous nuclear ribonucleoprotein H1; HOXC4, homeobox C4; HuR, Hu antigen R; IOX1, 5-carboxy-8-hydroxyquinoline; IRF, interferon regulatory factor; JAK, Janus kinase; KDM1A, lysine demethylase 1A; KDM4B, lysine demethylase 4B; lncRNA, long non-coding RNA; LSD1, lysine-specific histone demethylase 1; me, methylation; MEF2D, myocyte enhancer factor 2D; miRNA/miR, microRNA; MLH1, mutL homolog 1; MLL1, lysine methyltransferase 2A; p-, phosphorylated; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; PRMT5, protein arginine methyltransferase 5; SAHA, suberoylanilide hydroxamic acid; SNHG12, small nucleolar RNA host gene 12; TET2, tet methylcytosine dioxygenase 2; WDR5, WD repeat domain 5; YAP1, Yes associated protein 1.

2. Resistance mechanisms of ICIs targeting the PD-1/PD-L1 axis

ICIs that target the PD-1/PD-L1 axis have been extensively studied (31-33). Their mechanisms of action are mainly based on the following phenomena: i) Antigen-specific T cells are activated upon recognition of tumor antigens presented by major histocompatibility complex (MHC) on antigen-presenting cells, and subsequently, activated T cells release IFN-γ to upregulate PD-L1 expression on tumor cells (34); and ii) PD-L1 binds to PD-1 on the surface of T cells, triggering the negative regulation of the PD-1/PD-L1 axis, which will inhibit the antitumor effect of T cells (35,36). ICIs targeting the PD-1/PD-L1 axis reinvigorate T cells that were inactive because of the PD-1/PD-L1 signaling inhibition, and thereby, exert antitumor effects (36).

However, clinical data have indicated limited ICI efficacy in a large group of patients with primary resistance unresponsive to PD-1/PD-L1 blockade or acquired resistance after initial response (13). To the best of our knowledge, due to the complexity of antitumor immunity, the exact mechanism of resistance to ICIs targeting the PD-1/PD-L1 axis has not been fully elucidated or extensively reviewed. Resistance is triggered by various complex mechanisms (Fig. 2). Mechanisms leading to primary resistance include insufficient immunogenicity of tumor antigens formed by non-mutated proteins or mutant proteins that are not fully tolerated by T cells, irreversible exhaustion of T cells because of multiple inhibitory axes in the tumor microenvironment, which prevent tumor-specific T cells from becoming memory T cells, dysfunction of MHC class I complexes caused by β-2-microglobulin mutations, resistance to IFN-γ signaling caused by Janus kinase (JAK)1/2 mutations, and immunosuppression because of immunosuppressive cells, cytokines and tumor metabolites in the tumor microenvironment (37-43). The mechanisms of acquired resistance are primarily associated with tumor subclones, leading to increased numbers of tumor cells that can escape antitumor immunity, re-exhaustion of T cells because of persistently high antigen levels and activation of compensatory inhibitory signals (44-46). As previously mentioned, the mechanism of resistance to ICIs targeting the PD-1/PD-L1 axis is a complex intervention system that is constantly being updated with the increasing understanding of immunotherapy.

3. Regulation of PD-L1 expression in solid tumors by histone modifications

As one of the components of eukaryotic nucleosomes, histones can acquire a diverse set of post-translational modifications (47), of which acetylation and methylation are the most studied ones. In cancer cells, these modifications can alter the structural attributes of chromatin, regulate the function of nucleosomes, and affect the expression of specific genes, such as PD-L1 (48,49). Furthermore, histone modification, a dynamic and reversible process, is influenced by a number of chromatin-modifying enzymes that exist as multicomponent protein complexes (50). These enzymes are divided into writers, erasers and readers, according to their different functions (51). In multiple cancer types, including colon cancer and lung cancer, PD-L1 expression is affected by different chromatin-modifying enzymes, particularly histone deacetylases (HDAC) and histone methyltransferases (52,53).

Regulation of PD-L1 expression in solid tumors by histone acetylation

The acetylation of histones at their tail lysine residue can reduce the affinity of histones for DNA by neutralizing positive charges, which will facilitate chromatin opening and transcription (51). Enhancement of histone H3 acetylation in the PD-L1 promoter is involved in PD-L1 expression in various drug-resistant cancer cells, including those of breast cancer, lung cancer and hepatocellular carcinoma (12). Histone acetylation serves as a key mediator in the regulation of gene expression, the levels and states of which are influenced by the balance of factors opposing HDACs and histone acetyltransferases (HATs) (54). HDACs are involved in regulating the transcription of PD-L1 by regulating histone acetylation through removing acetyl groups of lysine residues from histone substrates (12).

HDAC3 is the key HDAC isoform responsible for regulating PD-L1 transcription in tumors (55). Inhibition of HDAC3 expression can increase IFN-γ production and PD-L1 promoter region histone acetylation, thereby activating PD-L1 transcription in tumor cells and increasing the levels of PD-L1 in dendritic cells in the tumor microenvironment (55,56). Furthermore, HDAC3 maintains PD-L1 expression by inhibiting histone H3 acetylation at the PD-L1 promoter in drug-resistant cells of lung cancer, breast cancer and hepatocellular carcinoma (12). As an oncogenic transcription factor, STAT3 is activated in various cancer types, such as pancreatic cancer, breast cancer and osteosarcoma, and thus, affects the expression and transcription of genes involved in cellular immune responses, proliferation and chemoresistance (57). HDAC3 upregulates PD-L1 expression in pancreatic cancer by intervening in the STAT3 signaling pathway (58). In primary melanoma, HDAC8 can inhibit PD-L1 expression by controlling the transcriptional activation of PD-L1 by acting on STAT3-containing transcriptional complexes (59). HDAC6 upregulates PD-L1 expression in melanoma and osteosarcoma by recruiting and activating the transcription factor STAT3 (60,61). In addition, HDAC6 expression is positively associated with PD-L1 expression in ovarian cancer (62). HDAC10, another member of the class IIB HDAC family, has been reported to be positively associated with PD-L1 expression in patients with lung cancer (63).

HDAC1/2, which belong to the class I HDAC family, can be recruited by tet methylcytosine dioxygenase 2 proteins to the PD-L1 promoter to deacetylate H3K27 acetylation, thereby inhibiting the transcription of PD-L1 in breast cancer (24). Additionally, HDAC2 promotes PD-L1 expression by upregulating the phosphorylation of JAK1, JAK2 and STAT1, as well as translocation of STAT1 to the nucleus and recruitment of STAT1 to the PD-L1 promoter (64). HDAC1 expression is consistently upregulated in tumor spheres derived from breast cancer and affects the epithelial-mesenchymal transition (EMT)-induced upregulation of PD-L1 expression (65). In addition, EMT-induced upregulation of PD-L1 expression in breast cancer is also affected by HATs (65). HATs are involved in histone acetylation by catalyzing the transfer of acetyl groups (54). HAT1 was the first HAT to be discovered, HAT1 expression is upregulated in various solid tumors and HAT1 acts as a transcription factor to regulate the expression of multiple genes (66,67). In pancreatic cancer, upregulation of HAT1 expression is not only associated with poor prognosis but can also enhance PD-L1 transcription by promoting the binding of bromodomain-containing 4 (BRD4)-containing complex to acetylated histone H4 (25).

HDAC inhibitors (HDACis) can inhibit HDAC-mediated deacetylation, leading to the hyperacetylation of histones and re-expression of epigenetically silenced genes (68). At present, only a few HDACis, such as vorinostat, romidepsin, belinostat and Panobinostat, have been approved by the FDA to treat malignancies, while other HDACis are undergoing various clinical trials as options for the treatment of malignancies (69). HDACis exert antitumor effects by inducing cell apoptosis, inhibiting angiogenesis, and regulating cell autophagy and immune responses; however, to the best of our knowledge, the mechanisms by which they regulate PD-L1 have not been well defined (70,71).

Class I HDACis can elevate PD-L1 expression in a variety of tumors, including chondrosarcoma, Hodgkin's lymphoma, melanoma, lung cancer, prostate cancer and colorectal cancer (52,71-77). Among them, chidamide can upregulate PD-L1 expression in chondrosarcoma by activating the transcription factor STAT1 (72). In addition, it could enhance the antigen presentation process in a chondrosarcoma mouse model to improve therapeutic efficacy (72). When suberoylanilide hydroxamic acid is used to treat prostate cancer cells, it can increase histone H3 acetylation of the CD274 promoter to induce CD274 transcription, leading to upregulation of PD-L1 expression (76). As a naturally occurring selective inhibitor of HDACs 1 and 2, romidepsin increases PD-L1 expression in colorectal cancer, mainly through the regulation of histone acetylation and the transcription factor BRD4 (52). Furthermore, HDAC6 inhibitors, as class II HDACis, can dose-dependently reduce PD-L1 expression in colorectal, lung and urothelial cancer (78-80). A study suggests that HDACis can enhance the response to immunotherapy via increasing tumor antigen levels and reactivation of proapoptotic genes (81). However, HDACis have side effects, such as lymphopenia, that limit the efficacy of immunotherapy (82).

Regulation of PD-L1 expression in solid tumors by histone methylation

Histone methylation is a reversible process on arginine and lysine residues: Arginine is symmetrically or asymmetrically methylated, while lysine can be monomethylated, dimethylated or trimethylated (83). Among these, H3K4, H3K36 and H3K79 are associated with transcriptional activation of genes, whereas H3K9, H3K27 and H4K20 are associated with the transcriptional repression of genes (83). For example, in colorectal cancer, the transcriptional upregulation of PD-L1 is positively associated with H3K4me3 and negatively associated with H3K9 tri-methylation (H3K9me3) (84). Inhibitory H3K9me3 and H3K27me3 also regulate PD-L1 expression in breast cancer tumor-forming cells (65).

Histone methylation is a complex modification process regulated by various methyltransferases and demethylases. Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric dimethylarginine of histone and non-histone proteins and is closely associated with tumor cell proliferation, invasion and metastasis (85). In cervical cancer, PRMT5 promotes the transcription of STAT1, and thus, PD-L1 expression through symmetric dimethylation of histone H3R2 (86). As one of the H3K4 methylation-specific histone methyltransferases, mixed lineage leukemia 1 catalyzes H3K4me3 to activate the transcription of PD-L1 in pancreatic cancer cells by directly binding to the CD274 promoter (26). Knockdown of WD repeat domain 5, a key component of the patient SE translocation 1/MLL histone methyltransferase complex, reduces IFN-γ-induced PD-L1 mRNA and protein levels in prostate cancer (87). EZH2 is a core component of the polycomb repressive complex 2 and possesses histone methyltransferase activity (88). In melanoma, EZH2 inactivation can lead to decreased PD-L1 mRNA levels (53). Similarly, EZH2 is also positively associated with PD-L1 levels in lung cancer tissues and regulates PD-L1 expression through hypoxia-inducible factor 1-α (89).

Lysine demethylase 4B (KDM4B) is a demethylase that acts on lysine, and its silencing can reduce PD-L1 expression by promoting H3K27me3 expression and reducing homeobox C4 (HOXC4) expression in colorectal cancer cells (90). In addition, lysine-specific histone demethylase 1 (LSD1) regulates the chromatin landscape and gene expression by demethylating proteins, such as histone H3 (91). HCI-2509, a noncompetitive highly potent reversible LSD1 inhibitor, upregulates PD-L1 expression in breast cancer cells in a dose-dependent manner (92). SP-2577, which is currently undergoing a phase I clinical trial, is also a potent and reversible LSD1 inhibitor that can promote PD-L1 expression in small cell carcinoma of the ovarian hypercalcemic type cells by inhibiting LSD1 (91). Based on these developments, LSD1 inhibition may be a promising epigenetic adjunctive therapy to ICIs. In addition, 5-carboxy-8-hydroxyquinoline (IOX1), a histone demethylase inhibitor that inhibits Jumonji domain 1A of histone demethylases, can downregulate PD-L1 expression in a concentration-dependent manner in various cancer cells, including CT26, HCT116 and MCF-7 cells (93). IOX1 could also reverse doxorubicin-induced upregulation of PD-L1 expression (93).

Regulation of PD-L1 expression in solid tumors by histone phosphorylation

Histone phosphorylation is the most abundant and dynamic modification during mitosis of tumor cells, and its occurrence alone or in dense clusters can have a great impact on the structure and function of modified proteins (94). A study has demonstrated that histone phosphorylation can dissociate readers of methylated histones without loss of epigenetic information (95). This allows histone phosphorylation to serve a functional role in initiating chromatin for reliable chromosome segregation and preventing genetic instability (96).

Among them, histone H3 phosphorylation is known as a common epigenetic modification that affects chromatin structure and gene transcription (97). Pyruvate kinase isoform M2 (PKM2), a rate-limiting enzyme in glycolysis, is a transcriptional coactivator of multiple target genes associated with tumor cell proliferation and metastasis, and can be stimulated by epidermal growth factor (EGF) to translocate to the nucleus (98). In hepatocellular carcinoma, EGF can induce phosphorylation of PKM2 at Ser37 and translocation of the PKM2 protein to the nucleus, and then phosphorylation of histone H3 at Thr11 to induce PD-L1 expression (30).

4. Regulation of PD-L1 expression in solid tumors by non-coding RNAs

Non-coding RNAs are an abundant component of the human transcriptome. Since ncRNAs have the ability to regulate gene expression, protein translation and growth pathways, they can regulate a variety of cellular processes, such as growth, differentiation and drug resistance, which are highly related to the occurrence and development of cancer (99). Furthermore, non-coding RNAs, particularly microRNAs (miRNAs/miRs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), can regulate the expression of immune genes, such as PD-L1, in a variety of tumors, thereby serving an important role in immunotherapy (100).

Regulation of PD-L1 expression in solid tumors by miRNAs

miRNAs are highly conserved small non-coding RNAs comprising 19-22 nucleotides that inhibit gene expression by binding to complementary nucleotides in the 3′ untranslated region (3′ UTR) of mRNA targets (101,102). The mechanism of this interaction occurs under both physiological and pathological conditions, and thus, serves an important role in a number of biological processes, including cell proliferation, metastasis, apoptosis and metabolism (103,104). Aberrant miRNA expression during tumorigenesis can affect several cancer-related signaling pathways and transcripts, thereby aberrantly expressed miRNAs are becoming important diagnostic markers and attractive therapeutic candidates for multiple cancer types (105). In addition, a study has indicated that miRNAs can exert profound regulatory effects on the expression levels of PD-L1 through complex regulatory mechanisms (106).

In lung cancer, elevated levels of PD-L1 promote cell proliferation, invasion, migration and immune escape, and contribute to chemoresistance (107). miR-3127-5p induces PD-L1 expression in lung cancer cells by promoting phosphorylation of STAT3 (107). PD-L1 serves as a common downstream target of miR-377-3p and miR-155-5p, and inhibiting their expression can directly lead to upregulated PD-L1 levels (27). Let-7 miRNA serves a tumor-suppressive role in multiple cancer types by participating in the post-transcriptional expression of PD-L1 and has been implicated in the regulation of tumor immunotherapy (28,108). Hong et al (109) reported that Let-7 miRNA could be enriched by probes in the 3′ UTR region of PD-L1 mRNA in lung cancer cells, and overexpression of Let-7 miRNA could inhibit PD-L1 mRNA expression in lung cancer cells (110). Similarly, overexpression of miR-140 can also suppress PD-L1 expression by directly binding to its 3′ UTR and participating in the miR-140/PD-L1/cyclin E pathway in lung cancer to regulate the cell cycle and proliferation (111).

The miR-200 family, consisting of five members, miR-200a, miR-200b, miR-200c, miR-429 and miR-141, has also been implicated in the regulation of PD-L1 and inhibition of tumor cell proliferation and migration (112). Among them, miR-200b may regulate PD-L1 expression in lung cancer cells and is negatively associated with PD-L1 expression in patients with lung cancer (113). miR-200c, which is located on chromosome 12p13, can inhibit PD-L1 upregulation in ovarian and breast cancer cells to slow cell proliferation (114,115). In breast cancer, high PD-L1 expression is associated with poor prognosis (116,117), and miR-92 can upregulate PD-L1 expression by promoting YAP1 phosphorylation (118). miR-5119 improved antitumor immunotherapy efficacy in a mouse breast cancer model, possibly by downregulating PD-L1 expression (119). Furthermore, miR-570-3p, miR-195 and miR-497 induce apoptosis in breast cancer cells by binding to the 3′ UTR to regulate CD274 expression (120,121). miR-3609 can also bind to the 3′ UTR of PD-L1 to regulate its expression and reverse the chemoresistance of breast cancer cells by blocking the PD-L1 immune checkpoint (122).

Exosomes, subcellular vesicles with a diameter of 30-150 nm, contain numerous miRNAs, mRNAs and functional proteins, which are released after fusion of multivesicular bodies with the cell surface (123). Therefore, the identification of exosome contents may provide more information about specific tumor biomarkers. As an important part of the tumor microenvironment, exosomes are one of the most important factors in promoting tumor metastasis and progression by regulating immune responses, promoting angiogenesis and blocking EMT (124). As one of the highly enriched miRNAs found in exosomes of breast cancer cells, miR-27a-3p can upregulate PD-L1 in macrophages and promote immune evasion of breast cancer cells by activating the PTEN-AKT/PI3K pathway (125). PTEN expression is also inhibited by miR-21 mediated by oral cancer exosomes, which upregulate PD-L1 expression (126). Exosomal miR-16-5p can specifically target and downregulate PD-L1 in gastric cancer cells and block the PD-1/PD-L1 checkpoint to inhibit gastric cancer cell proliferation, leading to T-cell activation (127). Furthermore, aberrant expression of PD-L1 in gastric cancer is associated with miR-105-5p and miR-570 (128,129). In addition, miR-105-5p suppresses PD-L1 expression by directly targeting important cis-acting regulatory regions in the PD-L1 3′ UTR to combat immune escape (128). Furthermore, guanine to cytosine mutations in the 3′ UTR region can disrupt miR-570 binding, leading to upregulation of PD-L1 expression (129).

In colorectal cancer, PD-L1 expression has been demonstrated to be regulated by several miRNAs, such as miR-15a, miR-148a-3p, miR-124 and miR-20b-5p (90,130-132). miR-15a potently represses HOXC4 transcription by targeting KDM4B in colorectal cancer cells, thereby reducing PD-L1 expression and ultimately inhibiting immune evasion in colorectal cancer cells (90). miR-148a-3p may directly bind to the 3′ UTR region of PD-L1 to reduce the level of PD-L1 on the surface of colorectal cancer cells to reduce T-cell apoptosis and restore its activity (130). It has been reported that the frequency and activity of regulatory T cells (Tregs) were increased in human cancer types and that PD-L1 may be involved in Treg development and enhance their immunosuppressive capacity (133,134). miR-124 can directly target a specific region in the PD-L1 3′ UTR to downregulate its expression and inhibit Treg differentiation, thereby promoting T cell-mediated anticancer responses in colorectal cancer cells (131). HLA complex group 18 (HCG18) serves an oncogenic role as a competitive endogenous RNA for several miRNAs (135). In colorectal cancer, HCG18 promotes proliferation, inhibits apoptosis, upregulates PD-L1 by sponging miR-20b-5p, enhances resistance to cetuximab, and inhibits CD8+ T-cell activation by targeting the miR-20b-5p/PD-L1 axis (132). In other cancer types of the digestive tract, several miRNAs exhibit inhibitory effects on the expression of PD-L1. Bian et al (136) found that miR-493 overexpression could downregulate PD-L1 expression in esophageal cancer. Transfection with miR-612 reduces PD-L1 expression in pancreatic cancer cells (137). In pancreatic cancer cells, miR-93 and miR-106b can inhibit the expression of PD-L1 at the mRNA and protein levels (138). A study has demonstrated that miR-329-3p inhibited PD-L1 expression by targeting and downregulating lysine demethylase 1A, and it enhanced the response of hepatocellular carcinoma cells to T cell-induced cytotoxic effects (139). Furthermore, miR-22 and miR-24 are negatively associated with plasma PD-L1 levels in renal cancer, suggesting that the miRNA network can suppress PD-L1 expression (140). Studies suggest that miRNA-based drugs (miRNA mimics or miRNA antagonists) are promising and may be a novel strategy for cancer treatment (141,142).

Regulation of PD-L1 expression in solid tumors by lncRNAs

lncRNAs, RNA transcripts of >200 nucleotides, do not have protein-coding potential, but appear to be less expressed than protein-coding genes and have more tissue-specific features (143,144). lncRNAs can target multiple mechanisms by affecting different genes, and their abnormal expression is associated with the occurrence of different diseases, particularly cancer (145). In particular, increasing evidence suggests that lncRNAs have significant potential in immunotherapy by regulating PD-L1 expression in the tumor microenvironment (146,147).

In breast cancer, lncRNA KRT19P3 may inhibit tumor progression by reducing PD-L1 expression in tumor cells and activating the tumor-killing potential of CD8+ T cells (148). However, lncRNA GATA3-AS1 can promote immune evasion of breast cancer cells by regulating COP9 signalosome subunit 5-mediated PD-L1 deubiquitination (149). In esophageal cancer and ovarian cancer, lncRNAs can also mediate immune escape by affecting PD-L1 expression (29,150,151). After binding to glutathione peroxidase 4, lncRNA OIP5-AS1 can trigger CD8+ T cell apoptosis by regulating PD-1/PD-L1, thus promoting immune escape of esophageal cancer cells (29). Furthermore, lncRNA HOTTIP upregulates PD-L1 expression in neutrophils by promoting the secretion of IL-6, thereby inhibiting T cell activity and antitumor immunity (150). Additionally, lncRNA PVT1 promotes PD-L1 expression in ovarian cancer by upregulating STAT3 phosphorylation levels (151). Furthermore, lncRNA small nucleolar RNA host gene 12 promotes non-small cell lung cancer (NSCLC) cell proliferation and immune escape by increasing the expression stability of PD-L1 through binding of the human antigen R gene (152).

A study has demonstrated that lncRNA IFITM4P induced PD-L1 expression in oral cancer via two mechanisms (153). First, in the nucleus, IFITM4P decreases PTEN transcription by enhancing lysine demethylase 5A binding to the PTEN promoter, thereby upregulating PD-L1 expression (153). Second, in the cytoplasm, IFITM4P acts as a scaffold, promoting SAM and SH3 domain containing 1 binding and phosphorylating transforming growth factor β-activated kinase 1, which in turn increases the phosphorylation of NF-κB, while inducing PD-L1 expression (153). The lncRNA HOTAIR promotes the immune escape of glioma cells by activating the NF-κB pathway to abnormally express PD-L1 (154). It has been reported that lncRNAs could regulate different biological processes, including gene expression and RNA metabolism, after binding to protein partners (155). The primary transcript of lncRNA INCR blocks inhibition of the neighboring gene PD-L1 by binding to heterogeneous nuclear ribonucleoprotein H1 (156). Notably, in colorectal cancer, lncRNA MIR17HG can increase PD-L1 expression levels by directly binding PD-L1 (157). Furthermore, when lncRNA SNHG29 expression is inhibited, PD-L1 expression is downregulated in colorectal cancer cells to promote antitumor immunity (147).

Regulation of PD-L1 expression in solid tumors by circRNAs

circRNAs comprise a large class of endogenous non-coding RNAs with covalently closed loops that function independently of linear transcripts transcribed from the same gene (158). circRNAs are mostly generated through a process of 'back splicing', in which downstream splice donor sites are covalently linked to upstream splice acceptor sites, and are abundant in the cytoplasm (159). On the one hand, circRNAs can act as transcriptional regulators, miRNA sponges or protein decoys to serve an important role in tumor development and metastasis (160,161). On the other hand, circRNAs can alter drug concentrations in tumor cells by regulating the expression levels of related genes, such as multidrug resistance-associated protein-1 and multidrug resistance gene 1, which affects the drug resistance of tumor cells, such as glioma and liver cancer cells (162). In a mouse model of NSCLC, combined anti-PD-L1 and hsa_circ_0003222 inhibitory therapy not only reduced the tumor volume, but hsa_circ_0003222 inhibition also reduced the anti-PD-L1 resistance of NSCLC cells in vivo (163).

5. Regulation of PD-L1 expression in solid tumors by DNA methylation

As the most extensively studied type of epigenetic modification necessary for the regulation of gene transcription, DNA methylation is a covalent modification of the nucleotide cytosine at the 5-position (164). Although it does not alter the DNA sequence, it has an important effect on gene expression and is often associated with gene silencing (165). A study has demonstrated that DNA hypomethylation may lead to the expression of PD-L1 and inhibitory cytokines, which can be immunosuppressive (166). Therefore, the analysis of the specific mechanism of DNA methylation in regulating PD-L1 gene expression may have important clinical and biological implications.

In gastric cancer, PD-L1 promoter methylation is associated with PD-L1 protein expression, lymph node stage and the prognosis of advanced gastric cancer (167). A study has demonstrated that patients with gastric cancer with a methylated PD-L1 promoter exhibited shorter PFS and OS times than those without a methylated PD-L1 promoter (167). DNA methylation is mainly catalyzed by a family of DNMTs (168). In addition, 5-azacytidine, as a DNMT inhibitor, can increase PD-L1 expression in gastric cancer MKN-45 cells, whereas gemcitabine, a DNA demethylation inhibitor, can inhibit PD-L1 expression in these cells (169). Chondrosarcomas do not typically express PD-L1 to act as an immune-cold tumor; however, DNMT inhibitors can induce PD-L1 protein expression (73). In sorafenib-resistant hepatocellular carcinoma, high DNMT1 expression is positively associated with upregulation of PD-L1 expression (170). Myocyte enhancer factor 2D (MEF2D) is a transcription factor involved in a number of tumorigenic processes, and the reduction of MEF2D methylation increases its binding to the PD-L1 promoter and elevates PD-L1 expression in hepatocellular carcinoma (139). In melanoma, DNMT3A is inversely associated with PD-L1 expression at both the mRNA and protein levels, and treatment with DNMT inhibitors strongly increases PD-L1 levels on the surface of melanoma cells (171). DNMT inhibitors may also augment the efficacy of PD-L1 blockade therapy in ovarian cancer (172). Li et al (173) evaluated the synergistic effect of DNMT3A and DNMT1 on PD-L1 expression in DU145 prostate cancer cells. Recombinant plasmids containing the C-terminal domains of DNMT1 and DNMT3A methyltransferases inhibit PD-L1 expression more potently than those containing DNMT3A alone (173).

After EMT, tumor cells have increased capacities for proliferation and metastasis by evading the immune system (174). Asgarova et al (175) found that, during EMT signaling in NSCLC, TGFβ1 induced PD-L1 promoter demethylation by reducing the content of DNMT1, leading to the expression of PD-L1. In epidermal growth factor receptor tyrosine kinase inhibitor-resistant NSCLC, methylation of the PD-L1 promoter may contribute to the downregulation of PD-L1 expression (176). In anti-PD-1/PD-L1 therapy, IFN-γ-induced PD-L1 expression predicts a higher response rate (175). Lai et al (177) reported that the IFN-γ-related genes interferon regulatory factor (IRF)-1 and IRF-7, which are hypermethylated in lung cancer tissues, were negatively associated with CD274 expression. The methylation inhibitor decitabine can demethylate IRF-1 and IRF-7, thereby restoring PD-L1 levels (177). In gliomas, increased methylation of the PD-L1 promoter downregulates the mRNA and protein expression levels of PD-L1 (178). Therefore, hypomethylation of the PD-L1 promoter mediates upregulation of PD-L1 expression (179). A similar relationship has been demonstrated in patients with breast and colorectal cancer: The higher the hypomethylation levels were, the higher the PD-L1 expression levels were (180). In addition, PD-L1 expression in breast cancer cells is also associated with BRCA1 promoter hypermethylation (181). In patients with colorectal cancer, PD-L1 expression is more readily observed in microsatellite unstable cancers caused by mutL homolog 1 promoter methylation (182). The DNMT inhibitor 5-azacytidine also inhibits the downregulation of PD-L1 mRNA and protein levels in colorectal cancer cells (183).

6. Conclusions

This review summarizes the most comprehensive understanding of epigenetic factors affecting PD-L1 expression in solid tumors, including histone modifications, noncoding RNAs and DNA methylation (Table I). In terms of their potential contribution to PD-L1 expression in solid tumors, studies of histone modifications have mostly focused on acetylation, methylation and phosphorylation (54,94). During this process, multiple chromatin-modifying enzymes, such as HDACs, HATs, histone methyltransferases and histone demethylases, regulate PD-L1 expression by affecting modifications that occur on lysine and arginine residues. Most studies on miRNAs have focused on their binding to the 3′ UTR of PD-L1 (109-111). As one of the key factors affecting PD-L1 expression, various miRNAs can inhibit PD-L1 expression by binding to the 3′ UTR of mRNAs. lncRNAs mainly act as upstream regulators of the PD-1/PD-L1 axis to affect antitumor immunity. Finally, research on DNA methylation has exclusively focused on its effect on the PD-L1 promoter, and hypomethylation of the PD-L1 promoter often leads to upregulation of PD-L1 expression, thereby exerting immunosuppressive effects (30).

A large number of preclinical studies have revealed the critical role of epigenetic factors in antitumor immune responses and reversal of immunosuppression, particularly in PD-L1/PD-1 blockade (72,91,172,184). The rational application of a combination of multiple epigenetic targeted drugs, including DNMT inhibitors and histone-modifying enzyme inhibitors, with anti-PD-L1 immunotherapy, represents an opportunity to improve antitumor efficacy, enhance response rates to PD-1/PD-L1 blocking antibodies and reverse drug resistance. However, combinations are still in the early stages of development and there are still certain problems. First, the additional toxicity afforded by these epigenetic molecules cannot be underestimated. Some epigenetic drugs have been used for a long time with manageable side effects; however, the side effects associated with ICIs have not been extensively studied, especially in long-term treatment (16). Second, although exosomes are rich in miRNAs, mRNAs and functional proteins, and usually serve an important role in the regulation of PD-L1 expression by epigenetic factors (125,127), current clinical studies of exosome-based PD-L1 modification are lacking. Finally, although studies suggest that upregulated PD-L1 expression may be partly related to the activity of miRNAs, it is not completely clear whether tumors with increased PD-L1 expression due to dysregulated miRNA expression also exhibit higher response rates to ICIs (27,128,129). The development of large-scale epigenetic marking studies and the continuous updating of testbed technologies may open the way to address these issues.

In conclusion, at present, a large amount of work is still required to explore epigenetic changes in depth. Future studies may develop more precise and effective drugs and treatment regimens by identifying more potential therapeutic targets and mechanisms of action. Epigenetic combination therapies will ultimately be combined in an optimal manner to enhance the effectiveness of anti-PD-L1 immunotherapy in solid tumors, improving the prognosis of patients.

Availability of data and materials

Not applicable.

Authors' contributions

The research project was designed by XM and CS, organized by XM, JW and BW, and reviewed and critiqued by CS. The first draft of the manuscript was written by XM. The content and grammar of the manuscript was revised by JW, BW, CL, LL and CS. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant nos. 81973677 and 82174222) and Shandong Province Natural Science Foundation (grant nos. ZR2021LZY015 and ZR202103030292).

Abbreviations:

PD-L1

programmed death ligand 1

PD-1

programmed cell death protein 1

OS

overall survival

PFS

progression-free survival

miRNA

microRNA

FDA

Food and Drug Administration

EZH2

enhancer of zeste homolog 2

DNMT

DNA methyltransferase

ICIs

immune checkpoint inhibitors

MHC

major histocompatibility complex

EMT

epithelial-mesenchymal transition

NSCLC

non-small cell lung cancer

3′UTR

3′untranslated region

HDACs

histone deacetylases

HATs

histone acetyltransferases

HDACis

HDAC inhibitors

LSD1

lysine-specific histone demethylase 1

H3K9me3

H3K9 tri-methylation

References

1 

Chen J, Jiang CC, Jin L and Zhang XD: Regulation of PD-L1: A novel role of pro-survival signalling in cancer. Ann Oncol. 27:409–416. 2016. View Article : Google Scholar

2 

Mellman I, Coukos G and Dranoff G: Cancer immunotherapy comes of age. Nature. 480:480–489. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Guan J, Lim KS, Mekhail T and Chang CC: Programmed death ligand-1 (PD-L1) expression in the programmed death receptor-1 (PD-1)/PD-L1 blockade: A key player against various cancers. Arch Pathol Lab Med. 141:851–861. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, et al: Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med. 8:793–800. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Yang F, Wang JF, Wang Y, Liu B and Molina JR: Comparative analysis of predictive biomarkers for PD-1/PD-L1 inhibitors in cancers: Developments and challenges. Cancers. 14:1092021. View Article : Google Scholar

6 

Liu D, Wang S and Bindeman W: Clinical applications of PD-L1 bioassays for cancer immunotherapy. J Hematol Oncol. 10:1102017. View Article : Google Scholar : PubMed/NCBI

7 

Wang Y, Zhang H, Liu C, Wang Z, Wu W, Zhang N, Zhang L, Hu J, Luo P, Zhang J, et al: Immune checkpoint modulators in cancer immunotherapy: Recent advances and emerging concepts. J Hematol Oncol. 15:1112022. View Article : Google Scholar : PubMed/NCBI

8 

Kim CG, Kim M, Hwang J, Kim ST, Jung M, Kim KH, Kim KH, Chang JS, Koom WS, Roh MR, et al: First-line pembrolizumab versus dabrafenib/trametinib treatment for BRAF V600-mutant advanced melanoma. J Am Acad Dermatol. Sep 3–2022.Epub ahead of print. View Article : Google Scholar

9 

Donne R and Lujambio A: The liver cancer immune microenvironment: Therapeutic Implications for hepatocellular carcinoma. Hepatology. Aug 21–2022.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI

10 

Sun C, Mezzadra R and Schumacher TN: Regulation and function of the PD-L1 checkpoint. Immunity. 48:434–452. 2018. View Article : Google Scholar : PubMed/NCBI

11 

Topalian SL, Drake CG and Pardoll DM: Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell. 27:450–461. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Wang H, Fu C, Du J, Wang H, He R, Yin X, Li H, Li X, Wang H, Li K, et al: Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells. J Exp Clin Cancer Res. 39:292020. View Article : Google Scholar : PubMed/NCBI

13 

Sharma P, Hu-Lieskovan S, Wargo JA and Ribas A: Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 168:707–723. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Burkitt K and Saloura V: Epigenetic modifiers as novel therapeutic targets and a systematic review of clinical studies investigating epigenetic inhibitors in head and neck cancer. Cancers (Basel). 13:52412021. View Article : Google Scholar

15 

Huo M, Zhang J, Huang W and Wang Y: Interplay among metabolism, epigenetic modifications, and gene expression in cancer. Front Cell Dev Biol. 9:7934282021. View Article : Google Scholar

16 

Perrier A, Didelot A, Laurent-Puig P, Blons H and Garinet S: Epigenetic mechanisms of resistance to immune checkpoint inhibitors. Biomolecules. 10:10612020. View Article : Google Scholar :

17 

Martínez-Cano J, Campos-Sánchez E and Cobaleda C: Epigenetic priming in immunodeficiencies. Front Cell Dev Biol. 7:1252019. View Article : Google Scholar : PubMed/NCBI

18 

Kuendgen A and Lübbert M: Current status of epigenetic treatment in myelodysplastic syndromes. Ann Hematol. 87:601–611. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Hoy SM: Tazemetostat: First approval. Drugs. 80:513–521. 2020. View Article : Google Scholar : PubMed/NCBI

20 

Li Y and Seto E: HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med. 6:a0268312016. View Article : Google Scholar : PubMed/NCBI

21 

Chen Y, Liu X, Li Y, Quan C, Zheng L and Huang K: Lung cancer therapy targeting histone methylation: Opportunities and challenges. Comput Struct Biotechnol J. 16:211–223. 2018. View Article : Google Scholar : PubMed/NCBI

22 

Lei Q, Wang D, Sun K, Wang L and Zhang Y: Resistance mechanisms of anti-PD1/PDL1 therapy in solid tumors. Front Cell Dev Biol. 8:6722020. View Article : Google Scholar : PubMed/NCBI

23 

O'Donnell JS, Long GV, Scolyer RA, Teng MW and Smyth MJ: Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev. 52:71–81. 2017. View Article : Google Scholar

24 

Shen Y, Liu L, Wang M, Xu B, Lyu R, Shi YG and Tan L: TET2 inhibits PD-L1 gene expression in breast cancer cells through histone deacetylation. Cancers (Basel). 13:22072021. View Article : Google Scholar

25 

Fan P, Zhao J, Meng Z, Wu H, Wang B, Wu H and Jin X: Overexpressed histone acetyltransferase 1 regulates cancer immunity by increasing programmed death-ligand 1 expression in pancreatic cancer. J Exp Clin Cancer Res. 38:472019. View Article : Google Scholar : PubMed/NCBI

26 

Lu C, Paschall AV, Shi H, Savage N, Waller JL, Sabbatini ME, Oberlies NH, Pearce C and Liu K: The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion. J Natl Cancer Inst. 109:djw2832017. View Article : Google Scholar :

27 

Xia R, Geng G, Yu X, Xu Z, Guo J, Liu H, Li N, Li Z, Li Y, Dai X, et al: LINC01140 promotes the progression and tumor immune escape in lung cancer by sponging multiple microRNAs. J Immunother Cancer. 9:e0027462021. View Article : Google Scholar : PubMed/NCBI

28 

Gilles ME and Slack FJ: Let-7 microRNA as a potential therapeutic target with implications for immunotherapy. Expert Opin Ther Targets. 22:929–939. 2018. View Article : Google Scholar : PubMed/NCBI

29 

Hou J, Huang Q, Fan Z, Sang H, Wu S, Cheng S and Li Q: LncRNA OIP5-AS1 knockdown facilitated the ferroptosis and immune evasion by modulating the GPX4 in oesophageal carcinoma. Comput Math Methods Med. 2022:81031982022. View Article : Google Scholar : PubMed/NCBI

30 

Wang X, Liang C, Yao X, Yang RH, Zhang ZS, Liu FY, Li WQ, Pei SH, Ma J, Xie SQ and Fang D: Corrigendum: PKM2-induced the phosphorylation of histone H3 contributes to EGF-Mediated PD-L1 transcription in HCC. Front Pharmacol. 12:7247992021. View Article : Google Scholar : PubMed/NCBI

31 

Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, et al: Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol. 37:1470–1478. 2019. View Article : Google Scholar : PubMed/NCBI

32 

Abiko K, Hamanishi J, Matsumura N and Mandai M: Dynamic host immunity and PD-L1/PD-1 blockade efficacy: Developments after 'IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer'. Br J Cancer. Sep 6–2022.Epub ahead of print. View Article : Google Scholar

33 

Mussafi O, Mei J, Mao W and Wan Y: Immune checkpoint inhibitors for PD-1/PD-L1 axis in combination with other immunotherapies and targeted therapies for non-small cell lung cancer. Front Oncol. 12:9484052022. View Article : Google Scholar : PubMed/NCBI

34 

Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, Zaretsky JM, Sun L, Hugo W, Wang X, et al: Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 29:37662019. View Article : Google Scholar : PubMed/NCBI

35 

Ribas A and Wolchok JD: Cancer immunotherapy using checkpoint blockade. Science. 359:1350–1355. 2018. View Article : Google Scholar : PubMed/NCBI

36 

Akinleye A and Rasool Z: Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol. 12:922019. View Article : Google Scholar : PubMed/NCBI

37 

Heemskerk B, Kvistborg P and Schumacher TN: The cancer antigenome. EMBO J. 32:194–203. 2013. View Article : Google Scholar :

38 

McLane LM, Abdel-Hakeem MS and Wherry EJ: CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 37:457–495. 2019. View Article : Google Scholar : PubMed/NCBI

39 

Zhang Z, Liu S, Zhang B, Qiao L and Zhang Y and Zhang Y: T cell dysfunction and exhaustion in cancer. Front Cell Dev Biol. 8:172020. View Article : Google Scholar : PubMed/NCBI

40 

Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, Bjorgaard SL, Hammond MR, Vitzthum H, Blackmon SM, et al: Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun. 8:11362017. View Article : Google Scholar : PubMed/NCBI

41 

Yeon Yeon S, Jung SH, Jo YS, Choi EJ, Kim MS, Chung YJ and Lee SH: Immune checkpoint blockade resistance-related B2M hotspot mutations in microsatellite-unstable colorectal carcinoma. Pathol Res Pract. 215:209–214. 2019. View Article : Google Scholar

42 

Ngiow SF, Young A, Jacquelot N, Yamazaki T, Enot D, Zitvogel L and Smyth MJ: A threshold level of intratumor CD8+ T-cell PD1 expression dictates therapeutic response to anti-PD1. Cancer Res. 75:3800–3811. 2015. View Article : Google Scholar : PubMed/NCBI

43 

Li X, Wenes M, Romero P, Huang SC, Fendt SM and Ho PC: Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 16:425–441. 2019. View Article : Google Scholar : PubMed/NCBI

44 

O'Donnell JS, Teng MWL and Smyth MJ: Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol. 16:151–167. 2019. View Article : Google Scholar

45 

Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, et al: Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 354:1160–1165. 2016. View Article : Google Scholar : PubMed/NCBI

46 

Theivanthiran B, Evans KS, DeVito NC, Plebanek M, Sturdivant M, Wachsmuth LP, Salama AK, Kang Y, Hsu D, Balko JM, et al: A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J Clin Invest. 130:2570–2586. 2020. View Article : Google Scholar : PubMed/NCBI

47 

Bowman GD and Poirier MG: Post-translational modifications of histones that influence nucleosome dynamics. Chem Rev. 115:2274–2295. 2015. View Article : Google Scholar :

48 

Bajbouj K, Al-Ali A, Ramakrishnan RK, Saber-Ayad M and Hamid Q: Histone modification in NSCLC: Molecular mechanisms and therapeutic targets. Int J Mol Sci. 22:117012021. View Article : Google Scholar : PubMed/NCBI

49 

Hu X, Lin Z, Wang Z and Zhou Q: Emerging role of PD-L1 modification in cancer immunotherapy. Am J Cancer Res. 11:3832–3840. 2021.PubMed/NCBI

50 

Greer EL and Shi Y: Histone methylation: A dynamic mark in health, disease and inheritance. Nat Rev Genet. 13:343–357. 2012. View Article : Google Scholar : PubMed/NCBI

51 

Li W, Wu H, Sui S, Wang Q, Xu S and Pang D: Targeting histone modifications in breast cancer: A precise weapon on the way. Front Cell Dev Biol. 9:7369352021. View Article : Google Scholar : PubMed/NCBI

52 

Shi Y, Fu Y, Zhang X, Zhao G, Yao Y, Guo Y, Ma G, Bai S and Li H: Romidepsin (FK228) regulates the expression of the immune checkpoint ligand PD-L1 and suppresses cellular immune functions in colon cancer. Cancer Immunol Immunother. 70:61–73. 2021. View Article : Google Scholar :

53 

Zingg D, Arenas-Ramirez N, Sahin D, Rosalia RA, Antunes AT, Haeusel J, Sommer L and Boyman O: The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep. 20:854–867. 2017. View Article : Google Scholar : PubMed/NCBI

54 

Gallagher SJ, Tiffen JC and Hersey P: Histone modifications, modifiers and readers in melanoma resistance to targeted and immune therapy. Cancers (Basel). 7:1959–1982. 2015. View Article : Google Scholar

55 

Deng S, Hu Q, Zhang H, Yang F, Peng C and Huang C: HDAC3 inhibition upregulates PD-L1 expression in B-cell lymphomas and augments the efficacy of anti-PD-L1 therapy. Mol Cancer Ther. 18:900–908. 2019. View Article : Google Scholar : PubMed/NCBI

56 

Mondello P, Tadros S, Teater M, Fontan L, Chang AY, Jain N, Yang H, Singh S, Ying HY, Chu CS, et al: Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma. Cancer Discov. 10:440–459. 2020. View Article : Google Scholar : PubMed/NCBI

57 

Hashimoto S, Hashimoto A, Muromoto R, Kitai Y, Oritani K and Matsuda T: Central roles of STAT3-mediated signals in onset and development of cancers: Tumorigenesis and immunosurveillance. Cells. 11:26182022. View Article : Google Scholar : PubMed/NCBI

58 

Hu G, He N, Cai C, Cai F, Fan P, Zheng Z and Jin X: HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer. Pancreatology. 19:383–389. 2019. View Article : Google Scholar : PubMed/NCBI

59 

Wang YF, Liu F, Sherwin S, Farrelly M, Yan XG, Croft A, Liu T, Jin L, Zhang XD and Jiang CC: Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells. J Invest Dermatol. 138:922–932. 2018. View Article : Google Scholar

60 

ML PPV, TK MP, ES JP, KVW CL, FC SD, et al: Essential role of HDAC6 in the regulation of PD-L1 in melanoma. Mol Oncol. 10:735–750. 2016. View Article : Google Scholar

61 

Keremu A, Aimaiti A, Liang Z and Zou X: Role of the HDAC6/STAT3 pathway in regulating PD-L1 expression in osteosarcoma cell lines. Cancer Chemother Pharmacol. 83:255–264. 2019. View Article : Google Scholar

62 

Yano M, Katoh T, Miyazawa M, Miyazawa M, Ogane N, Miwa M, Hasegawa K, Narahara H and Yasuda M: Clinicopathological correlation of ARID1A status with HDAC6 and its related factors in ovarian clear cell carcinoma. Sci Rep. 9:23972019. View Article : Google Scholar : PubMed/NCBI

63 

Liu X, Wang Y, Zhang R, Jin T, Qu L, Jin Q, Zheng J, Sun J, Wu Z, Wang L, et al: HDAC10 is positively associated with PD-L1 expression and poor prognosis in patients with NSCLC. Front Oncol. 10:4852020. View Article : Google Scholar : PubMed/NCBI

64 

Xu P, Xiong W, Lin Y, Fan L, Pan H and Li Y: Histone deacetylase 2 knockout suppresses immune escape of triple-negative breast cancer cells via downregulating PD-L1 expression. Cell Death Dis. 12:7792021. View Article : Google Scholar : PubMed/NCBI

65 

Darvin P, Sasidharan Nair V and Elkord E: PD-L1 expression in human breast cancer stem cells is epigenetically regulated through posttranslational histone modifications. J Oncol. 2019:39589082019. View Article : Google Scholar : PubMed/NCBI

66 

Makowski AM, Dutnall RN and Annunziato AT: Effects of acetylation of histone H4 at lysines 8 and 16 on activity of the Hat1 histone acetyltransferase. J Biol Chem. 276:43499–43502. 2001. View Article : Google Scholar : PubMed/NCBI

67 

Jin X, Tian S and Li P: Histone acetyltransferase 1 promotes cell proliferation and induces cisplatin resistance in hepatocellular carcinoma. Oncol Res. 25:939–946. 2017. View Article : Google Scholar

68 

Halaburková A, Jendželovský R, Kovaľ J, Herceg Z, Fedoročko P and Ghantous A: Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A. Clin Epigenetics. 9:622017. View Article : Google Scholar :

69 

Maccallini C, Ammazzalorso A, De Filippis B, Fantacuzzi M, Giampietro L and Amoroso R: HDAC inhibitors for the therapy of triple negative breast cancer. Pharmaceuticals (Basel). 15:6672022. View Article : Google Scholar

70 

Knox T, Sahakian E, Banik D, Hadley M, Palmer E, Noonepalle S, Kim J, Powers J, Gracia-Hernandez M, Oliveira V, et al: Author correction: Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells. Sci Rep. 9:148242019. View Article : Google Scholar : PubMed/NCBI

71 

Briere D, Sudhakar N, Woods DM, Hallin J, Engstrom LD, Aranda R, Chiang H, Sodré AL, Olson P, Weber JS and Christensen JG: The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy. Cancer Immunol Immunother. 67:381–392. 2018. View Article : Google Scholar

72 

Que Y, Zhang XL, Liu ZX, Zhao JJ, Pan QZ, Wen XZ, Xiao W, Xu BS, Hong DC, Guo TH, et al: Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma. J Immunother Cancer. 9:e0016962021. View Article : Google Scholar : PubMed/NCBI

73 

Sheikh TN, Chen X, Xu X, McGuire JT, Ingham M, Lu C and Schwartz GK: Growth inhibition and induction of innate immune signaling of chondrosarcomas with epigenetic inhibitors. Mol Cancer Ther. 20:2362–2371. 2021. View Article : Google Scholar : PubMed/NCBI

74 

Huang R, Zhang X, Min Z, Shadia AS, Yang S and Liu X: MGCD0103 induces apoptosis and simultaneously increases the expression of NF-κB and PD-L1 in classical Hodgkin's lymphoma. Exp Ther Med. 16:3827–3834. 2018.PubMed/NCBI

75 

Woods DM, Sodré AL, Villagra A, Sarnaik A, Sotomayor EM and Weber J: HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res. 3:1375–1385. 2015. View Article : Google Scholar : PubMed/NCBI

76 

Liu J, He D, Cheng L, Huang C, Zhang Y, Rao X, Kong Y, Li C, Zhang Z, Liu J, et al: p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer. Oncogene. 39:3939–3951. 2020. View Article : Google Scholar : PubMed/NCBI

77 

Bissonnette RP, Cesario RM, Goodenow B, Shojaei F and Gillings M: The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors. BMC Cancer. 21:9692021. View Article : Google Scholar : PubMed/NCBI

78 

Chen MC, Lin YC, Liao YH, Liou JP and Chen CH: MPT0G612, a novel HDAC6 inhibitor, induces apoptosis and suppresses IFN-γ-induced programmed death-ligand 1 in human colorectal carcinoma cells. Cancers (Basel). 11:16172019. View Article : Google Scholar

79 

Shin HS, Choi J, Lee J and Lee SY: Histone deacetylase as a valuable predictive biomarker and therapeutic target in immunotherapy for non-small cell lung cancer. Cancer Res Treat. 54:458–468. 2022. View Article : Google Scholar

80 

Kuroki H, Anraku T, Kazama A, Shirono Y, Bilim V and Tomita Y: Histone deacetylase 6 inhibition in urothelial cancer as a potential new strategy for cancer treatment. Oncol Lett. 21:642021. View Article : Google Scholar

81 

Hai R, Yang D, Zheng F, Wang W, Han X, Bode AM and Luo X: The emerging roles of HDACs and their therapeutic implications in cancer. Eur J Pharmacol. 931:1752162022. View Article : Google Scholar : PubMed/NCBI

82 

Xia C, Leon-Ferre R, Laux D, Deutsch J, Smith BJ, Frees M and Milhem M: Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide). Cancer Chemother Pharmacol. 74:691–697. 2014. View Article : Google Scholar : PubMed/NCBI

83 

Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I and Zhao K: High-resolution profiling of histone methylations in the human genome. Cell. 129:823–837. 2007. View Article : Google Scholar : PubMed/NCBI

84 

Sasidharan Nair V, Saleh R, Toor SM, Taha RZ, Ahmed AA, Kurer MA, Murshed K, Abu Nada M and Elkord E: Epigenetic regulation of immune checkpoints and T cell exhaustion markers in tumor-infiltrating T cells of colorectal cancer patients. Epigenomics. 12:1871–1882. 2020. View Article : Google Scholar : PubMed/NCBI

85 

Bedford MT and Richard S: Arginine methylation an emerging regulator of protein function. Mol Cell. 18:263–272. 2005. View Article : Google Scholar : PubMed/NCBI

86 

Jiang Y, Yuan Y, Chen M, Li S, Bai J, Zhang Y, Sun Y, Wang G, Xu H, Wang Z, et al: PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression. Theranostics. 11:9162–9176. 2021. View Article : Google Scholar : PubMed/NCBI

87 

Zhou Q, Chen X, He H, Peng S, Zhang Y, Zhang J, Cheng L, Liu S, Huang M, Xie R, et al: WD repeat domain 5 promotes chemoresistance and programmed death-ligand 1 expression in prostate cancer. Theranostics. 11:4809–4824. 2021. View Article : Google Scholar : PubMed/NCBI

88 

Kim KH and Roberts CW: Targeting EZH2 in cancer. Nat Med. 22:128–134. 2016. View Article : Google Scholar : PubMed/NCBI

89 

Zhao Y, Wang XX, Wu W, Long H, Huang J, Wang Z, Li T, Tang S, Zhu B and Chen D: EZH2 regulates PD-L1 expression via HIF-1α in non-small cell lung cancer cells. Biochem Biophys Res Commun. 517:201–209. 2019. View Article : Google Scholar : PubMed/NCBI

90 

Liu L, Yu T, Jin Y, Mai W, Zhou J and Zhao C: MicroRNA-15a carried by mesenchymal stem cell-derived extracellular vesicles inhibits the immune evasion of colorectal cancer cells by regulating the KDM4B/HOXC4/PD-L1 axis. Front Cell Dev Biol. 9:6298932021. View Article : Google Scholar : PubMed/NCBI

91 

Soldi R, Ghosh Halder T, Weston A, Thode T, Drenner K, Lewis R, Kaadige MR, Srivastava S, Daniel Ampanattu S, Rodriguez Del Villar R, et al: The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer. PLoS One. 15:e02357052020. View Article : Google Scholar : PubMed/NCBI

92 

Qin Y, Vasilatos SN, Chen L, Wu H, Cao Z, Fu Y, Huang M, Vlad AM, Lu B, Oesterreich S, et al: Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade. Oncogene. 38:390–405. 2019. View Article : Google Scholar :

93 

Liu J, Zhao Z, Qiu N, Zhou Q, Wang G, Jiang H, Piao Y, Zhou Z, Tang J and Shen Y: Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy. Nat Commun. 12:24252021. View Article : Google Scholar : PubMed/NCBI

94 

Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, et al: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 3:ra32010. View Article : Google Scholar : PubMed/NCBI

95 

Schmitz ML, Higgins JMG and Seibert M: Priming chromatin for segregation: Functional roles of mitotic histone modifications. Cell Cycle. 19:625–641. 2020. View Article : Google Scholar : PubMed/NCBI

96 

Santaguida S and Amon A: Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat Rev Mol Cell Biol. 16:473–485. 2015. View Article : Google Scholar : PubMed/NCBI

97 

Cerutti H and Casas-Mollano JA: Histone H3 phosphorylation: Universal code or lineage specific dialects? Epigenetics. 4:71–75. 2009. View Article : Google Scholar : PubMed/NCBI

98 

Chen S, Youhong T, Tan Y, He Y, Ban Y, Cai J, Li X, Xiong W, Zeng Z, Li G, et al: EGFR-PKM2 signaling promotes the metastatic potential of nasopharyngeal carcinoma through induction of FOSL1 and ANTXR2. Carcinogenesis. 41:723–733. 2020. View Article : Google Scholar :

99 

Wang WT, Han C, Sun YM, Chen TQ and Chen YQ: Noncoding RNAs in cancer therapy resistance and targeted drug development. J Hematol Oncol. 12:552019. View Article : Google Scholar : PubMed/NCBI

100 

Kaur M, Kaur B, Konar M and Sharma S: Noncoding RNAs as novel immunotherapeutic tools against cancer. Adv Protein Chem Struct Biol. 129:135–161. 2022. View Article : Google Scholar : PubMed/NCBI

101 

Rolfo C, Fanale D, Hong DS, Tsimberidou AM, Piha-Paul SA, Pauwels P, Van Meerbeeck JP, Caruso S, Bazan V, Cicero G, et al: Impact of microRNAs in resistance to chemotherapy and novel targeted agents in non-small cell lung cancer. Curr Pharm Biotechnol. 15:475–485. 2014. View Article : Google Scholar : PubMed/NCBI

102 

Schanza LM, Seles M, Stotz M, Fosselteder J, Hutterer GC, Pichler M and Stiegelbauer V: MicroRNAs associated with Von Hippel-Lindau pathway in renal cell carcinoma: A comprehensive review. Int J Mol Sci. 18:24952017. View Article : Google Scholar

103 

Forterre A, Komuro H, Aminova S and Harada M: A comprehensive review of cancer MicroRNA therapeutic delivery strategies. Cancers (Basel). 12:18522020. View Article : Google Scholar

104 

Anastasiadou E, Faggioni A, Trivedi P and Slack FJ: The nefarious nexus of noncoding RNAs in cancer. Int J Mol Sci. 19:20722018. View Article : Google Scholar :

105 

Shi C and Zhang Z: The prognostic value of the miR-200 family in ovarian cancer: A meta-analysis. Acta Obstet Gynecol Scand. 95:505–512. 2016. View Article : Google Scholar : PubMed/NCBI

106 

Cortez MA, Anfossi S, Ramapriyan R, Menon H, Atalar SC, Aliru M, Welsh J and Calin GA: Role of miRNAs in immune responses and immunotherapy in cancer. Genes Chromosomes Cancer. 58:244–253. 2019. View Article : Google Scholar :

107 

Tang D, Zhao D, Wu Y, Yao R, Zhou L, Lu L, Gao W and Sun Y: The miR-3127-5p/p-STAT3 axis up-regulates PD-L1 inducing chemoresistance in non-small-cell lung cancer. J Cell Mol Med. 22:3847–3856. 2018. View Article : Google Scholar : PubMed/NCBI

108 

Chen Y, Xie C, Zheng X, Nie X, Wang Z, Liu H and Zhao Y: LIN28/let-7/PD-L1 pathway as a target for cancer immunotherapy. Cancer Immunol Res. 7:487–497. 2019. View Article : Google Scholar : PubMed/NCBI

109 

Hong W, Xue M, Jiang J, Zhang Y and Gao X: Circular RNA circ-CPA4/let-7 miRNA/PD-L1 axis regulates cell growth, stemness, drug resistance and immune evasion in non-small cell lung cancer (NSCLC). J Exp Clin Cancer Res. 39:1492020. View Article : Google Scholar

110 

Zhang Q, Pan J, Xiong D, Wang Y, Miller MS, Sei S, Shoemaker RH, Izzotti A and You M: Pulmonary aerosol delivery of Let-7b microRNA confers a striking inhibitory effect on lung carcinogenesis through targeting the tumor immune microenvironment. Adv Sci (Weinh). 8:e21006292021. View Article : Google Scholar

111 

Xie WB, Liang LH, Wu KG, Wang LX, He X, Song C, Wang YQ and Li YH: MiR-140 expression regulates cell proliferation and targets PD-L1 in NSCLC. Cell Physiol Biochem. 46:654–663. 2018. View Article : Google Scholar : PubMed/NCBI

112 

Jo H, Shim K and Jeoung D: Potential of the miR-200 family as a target for developing anti-cancer therapeutics. Int J Mol Sci. 23:58812022. View Article : Google Scholar : PubMed/NCBI

113 

Katakura S, Kobayashi N, Hashimoto H, Kamimaki C, Tanaka K, Kubo S, Nakashima K, Teranishi S, Manabe S, Watanabe K, et al: MicroRNA-200b is a potential biomarker of the expression of PD-L1 in patients with lung cancer. Thorac Cancer. 11:2975–2982. 2020. View Article : Google Scholar : PubMed/NCBI

114 

Anastasiadou E, Messina E, Sanavia T, Mundo L, Farinella F, Lazzi S, Megiorni F, Ceccarelli S, Pontecorvi P, Marampon F, et al: MiR-200c-3p contrasts PD-L1 induction by combinatorial therapies and slows proliferation of epithelial ovarian cancer through downregulation of β-catenin and c-Myc. Cells. 10:5192021. View Article : Google Scholar

115 

Rogers TJ, Christenson JL, Greene LI, O'Neill KI, Williams MM, Gordon MA, Nemkov T, D'Alessandro A, Degala GD, Shin J, et al: Reversal of triple-negative breast cancer EMT by miR-200c decreases tryptophan catabolism and a program of immunosuppression. Mol Cancer Res. 17:30–41. 2019. View Article : Google Scholar

116 

Yao Y, Kong X, Liu R, Xu F, Liu G and Sun C: Development of a novel immune-related gene prognostic index for breast cancer. Front Immunol. 13:8450932022. View Article : Google Scholar : PubMed/NCBI

117 

Samanta D, Park Y, Ni X, Li H, Zahnow CA, Gabrielson E, Pan F and Semenza GL: Chemotherapy induces enrichment of CD47+/CD73+/PDL1+ immune evasive triple-negative breast cancer cells. Proc Natl Acad Sci USA. 115:E1239–E1248. 2018.

118 

Dou D, Ren X, Han M, Xu X, Ge X, Gu Y and Wang X: Cancer-associated fibroblasts-derived exosomes suppress immune cell function in breast cancer via the miR-92/PD-L1 pathway. Front Immunol. 11:20262020. View Article : Google Scholar : PubMed/NCBI

119 

Zhang M, Shi Y, Zhang Y, Wang Y, Alotaibi F, Qiu L, Wang H, Peng S, Liu Y, Li Q, et al: miRNA-5119 regulates immune checkpoints in dendritic cells to enhance breast cancer immunotherapy. Cancer Immunol Immunother. 69:951–967. 2020. View Article : Google Scholar : PubMed/NCBI

120 

Wang LL, Huang WW, Huang J, Huang RF, Li NN, Hong Y, Chen ML, Wu F and Liu J: Protective effect of hsa-miR-570-3p targeting CD274 on triple negative breast cancer by blocking PI3K/AKT/mTOR signaling pathway. Kaohsiung J Med Sci. 36:581–591. 2020. View Article : Google Scholar : PubMed/NCBI

121 

Yang L, Cai Y, Zhang D, Sun J, Xu C, Zhao W, Jiang W and Pan C: miR-195/miR-497 regulate CD274 expression of immune regulatory ligands in triple-negative breast cancer. J Breast Cancer. 21:371–381. 2018. View Article : Google Scholar

122 

Li D, Wang X, Yang M, Kan Q and Duan Z: miR3609 sensitizes breast cancer cells to adriamycin by blocking the programmed death-ligand 1 immune checkpoint. Exp Cell Res. 380:20–28. 2019. View Article : Google Scholar : PubMed/NCBI

123 

Liu J, Ren L, Li S, Li W, Zheng X, Yang Y, Fu W, Yi J, Wang J and Du G: The biology, function, and applications of exosomes in cancer. Acta Pharm Sin B. 11:2783–2797. 2021. View Article : Google Scholar : PubMed/NCBI

124 

Mathivanan S, Ji H and Simpson RJ: Exosomes: Extracellular organelles important in intercellular communication. J Proteomics. 73:1907–1920. 2010. View Article : Google Scholar : PubMed/NCBI

125 

Yao X, Tu Y, Xu Y, Guo Y, Yao F and Zhang X: Endoplasmic reticulum stress-induced exosomal miR-27a-3p promotes immune escape in breast cancer via regulating PD-L1 expression in macrophages. J Cell Mol Med. 24:9560–9573. 2020. View Article : Google Scholar : PubMed/NCBI

126 

Li L, Cao B, Liang X, Lu S, Luo H, Wang Z, Wang S, Jiang J, Lang J and Zhu G: Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes. Oncogene. 38:2830–2843. 2019. View Article : Google Scholar

127 

Li Z, Suo B, Long G, Gao Y, Song J, Zhang M, Feng B, Shang C and Wang D: Exosomal miRNA-16-5p derived from M1 macrophages enhances T cell-dependent immune response by regulating PD-L1 in gastric cancer. Front Cell Dev Biol. 8:5726892020. View Article : Google Scholar : PubMed/NCBI

128 

Miliotis C and Slack FJ: miR-105-5p regulates PD-L1 expression and tumor immunogenicity in gastric cancer. Cancer Lett. 518:115–126. 2021. View Article : Google Scholar : PubMed/NCBI

129 

Wang W, Sun J, Li F, Li R, Gu Y, Liu C, Yang P, Zhu M, Chen L, Tian W, et al: A frequent somatic mutation in CD274 3′-UTR leads to protein over-expression in gastric cancer by disrupting miR-570 binding. Hum Mutat. 33:480–484. 2012. View Article : Google Scholar

130 

Ashizawa M, Okayama H, Ishigame T, Thar Min AK, Saito K, Ujiie D, Murakami Y, Kikuchi T, Nakayama Y, Noda M, et al: miRNA-148a-3p regulates immunosuppression in DNA mismatch repair-deficient colorectal cancer by targeting PD-L1. Mol Cancer Res. 17:1403–1413. 2019. View Article : Google Scholar : PubMed/NCBI

131 

Roshani Asl E, Rasmi Y and Baradaran B: MicroRNA-124-3p suppresses PD-L1 expression and inhibits tumorigenesis of colorectal cancer cells via modulating STAT3 signaling. J Cell Physiol. 236:7071–7087. 2021. View Article : Google Scholar : PubMed/NCBI

132 

Xu YJ, Zhao JM, Ni XF, Wang W, Hu WW and Wu CP: LncRNA HCG18 suppresses CD8+ T cells to confer resistance to cetuximab in colorectal cancer via miR-20b-5p/PD-L1 axis. Epigenomics. 13:1281–1297. 2021.PubMed/NCBI

133 

Whiteside TL: The role of regulatory T cells in cancer immunology. Immunotargets Ther. 4:159–171. 2015. View Article : Google Scholar : PubMed/NCBI

134 

Cai J, Wang D, Zhang G and Guo X: The role Of PD-1/PD-L1 axis in treg development and function: Implications for cancer immunotherapy. Onco Targets Ther. 12:8437–8445. 2019. View Article : Google Scholar : PubMed/NCBI

135 

Li S, Wu T, Zhang D, Sun X and Zhang X: The long non-coding RNA HCG18 promotes the growth and invasion of colorectal cancer cells through sponging miR-1271 and upregulating MTDH/Wnt/β-catenin. Clin Exp Pharmacol Physiol. 47:703–712. 2020. View Article : Google Scholar

136 

Bian W, Li Y, Zhu H, Gao S, Niu R, Wang C, Zhang H, Qin X and Li S: miR-493 by regulating of c-Jun targets Wnt5a/PD-L1-inducing esophageal cancer cell development. Thorac Cancer. 12:1579–1588. 2021. View Article : Google Scholar : PubMed/NCBI

137 

Javadrashid D, Mohammadzadeh R, Baghbanzadeh A, Safaee S, Amini M, Lotfi Z, Baghbani E, Khaze Shahgoli V and Baradaran B: Simultaneous microRNA-612 restoration and 5-FU treatment inhibit the growth and migration of human PANC-1 pancreatic cancer cells. EXCLI J. 20:160–173. 2021.PubMed/NCBI

138 

Cioffi M, Trabulo SM, Vallespinos M, Raj D, Kheir TB, Lin ML, Begum J, Baker AM, Amgheib A, Saif J, et al: The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1. Oncotarget. 8:21609–21625. 2017. View Article : Google Scholar : PubMed/NCBI

139 

Wang Y and Cao K: KDM1A promotes immunosuppression in hepatocellular carcinoma by regulating PD-L1 through demethylating MEF2D. J Immunol Res. 2021:99650992021. View Article : Google Scholar : PubMed/NCBI

140 

Incorvaia L, Fanale D, Badalamenti G, Brando C, Bono M, De Luca I, Algeri L, Bonasera A, Corsini LR, Scurria S, et al: A 'lymphocyte MicroRNA signature' as predictive biomarker of immunotherapy response and plasma PD-1/PD-L1 expression levels in patients with metastatic renal cell carcinoma: Pointing towards epigenetic reprogramming. Cancers (Basel). 12:33962020. View Article : Google Scholar

141 

Adil MS, Khulood D and Somanath PR: Targeting Akt-associated microRNAs for cancer therapeutics. Biochem Pharmacol. 189:1143842021. View Article : Google Scholar :

142 

Xue J, Yang J, Luo M, Cho WC and Liu X: MicroRNA-targeted therapeutics for lung cancer treatment. Expert Opin Drug Discov. 12:141–157. 2017. View Article : Google Scholar

143 

Pal S, Garg M and Pandey AK: Deciphering the mounting complexity of the p53 regulatory network in correlation to long non-coding RNAs (lncRNAs) in ovarian cancer. Cells. 9:5272020. View Article : Google Scholar :

144 

Chen X, Tang FR, Arfuso F, Cai WQ, Ma Z, Yang J and Sethi G: The emerging role of long non-coding RNAs in the metastasis of hepatocellular carcinoma. Biomolecules. 10:662019. View Article : Google Scholar

145 

Vafadar A, Shabaninejad Z, Movahedpour A, Mohammadi S, Fathullahzadeh S, Mirzaei HR, Namdar A, Savardashtaki A and Mirzaei H: Long non-coding RNAs as epigenetic regulators in cancer. Curr Pharm Des. 25:3563–3577. 2019. View Article : Google Scholar : PubMed/NCBI

146 

Yi K, Cui X, Liu X, Wang Y, Zhao J, Yang S, Xu C, Yang E, Xiao M, Hong B, et al: PTRF/Cavin-1 as a novel RNA-binding protein expedites the NF-κB/PD-L1 axis by stabilizing lncRNA NEAT1, contributing to tumorigenesis and immune evasion in glioblastoma. Front Immunol. 12:8027952022. View Article : Google Scholar

147 

Ni W, Mo H, Liu Y, Xu Y, Qin C, Zhou Y, Li Y, Li Y, Zhou A, Yao S, et al: Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation. Mol Ther. 29:2995–3010. 2021. View Article : Google Scholar : PubMed/NCBI

148 

Fan Y, Dong X, Li M, Liu P, Zheng J, Li H and Zhang Y: LncRNA KRT19P3 is involved in breast cancer cell proliferation, migration and invasion. Front Oncol. 11:7990822022. View Article : Google Scholar : PubMed/NCBI

149 

Zhang M, Wang N, Song P, Fu Y, Ren Y, Li Z and Wang J: LncRNA GATA3-AS1 facilitates tumour progression and immune escape in triple-negative breast cancer through destabilization of GATA3 but stabilization of PD-L1. Cell Prolif. 53:e128552020. View Article : Google Scholar : PubMed/NCBI

150 

Shang A, Wang W, Gu C, Chen C, Zeng B, Yang Y, Ji P, Sun J, Wu J, Lu W, et al: Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils. J Exp Clin Cancer Res. 38:4112019. View Article : Google Scholar : PubMed/NCBI

151 

Chen Y, Li F, Li D, Liu W and Zhang L: Atezolizumab and blockade of LncRNA PVT1 attenuate cisplatin resistant ovarian cancer cells progression synergistically via JAK2/STAT3/PD-L1 pathway. Clin Immunol. 227:1087282021. View Article : Google Scholar : PubMed/NCBI

152 

Huang Y, Xia L, Tan X, Zhang J, Zeng W, Tan B, Yu X, Fang W and Yang Z: Molecular mechanism of lncRNA SNHG12 in immune escape of non-small cell lung cancer through the HuR/PD-L1/USP8 axis. Cell Mol Biol Lett. 27:432022. View Article : Google Scholar : PubMed/NCBI

153 

Shi L, Yang Y, Li M, Li C, Zhou Z, Tang G, Wu L, Yao Y, Shen X, Hou Z and Jia H: LncRNA IFITM4P promotes immune escape by up-regulating PD-L1 via dual mechanism in oral carcinogenesis. Mol Ther. 30:1564–1577. 2022. View Article : Google Scholar : PubMed/NCBI

154 

Wang Y, Yi K, Liu X, Tan Y, Jin W, Li Y, Zhou J, Wang H and Kang C: HOTAIR up-regulation activates NF-κB to induce immunoescape in gliomas. Front Immunol. 12:7854632021. View Article : Google Scholar

155 

Atianand MK, Hu W, Satpathy AT, Shen Y, Ricci EP, Alvarez-Dominguez JR, Bhatta A, Schattgen SA, McGowan JD, Blin J, et al: A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to restrain inflammation. Cell. 165:1672–1685. 2016. View Article : Google Scholar : PubMed/NCBI

156 

Mineo M, Lyons SM, Zdioruk M, von Spreckelsen N, Ferrer-Luna R, Ito H, Alayo QA, Kharel P, Giantini Larsen A, Fan WY, et al: Tumor interferon signaling is regulated by a lncRNA INCR1 transcribed from the PD-L1 locus. Mol Cell. 78:1207–1223.e8. 2020. View Article : Google Scholar : PubMed/NCBI

157 

Xu J, Meng Q, Li X, Yang H, Xu J, Gao N, Sun H, Wu S, Familiari G, Relucenti M, et al: Long noncoding RNA MIR17HG promotes colorectal cancer progression via miR-17-5p. Cancer Res. 79:4882–4895. 2019. View Article : Google Scholar : PubMed/NCBI

158 

Yin L, Tang Y and Yuan Y: An overview of the advances in research on the molecular function and specific role of circular RNA in cardiovascular diseases. Biomed Res Int. 2022:51541222022. View Article : Google Scholar : PubMed/NCBI

159 

Verduci L, Tarcitano E, Strano S, Yarden Y and Blandino G: CircRNAs: Role in human diseases and potential use as biomarkers. Cell Death Dis. 12:4682021. View Article : Google Scholar : PubMed/NCBI

160 

Dong W, Dai ZH, Liu FC, Guo XG, Ge CM, Ding J, Liu H and Yang F: The RNA-binding protein RBM3 promotes cell proliferation in hepatocellular carcinoma by regulating circular RNA SCD-circRNA 2 production. EBioMedicine. 45:155–167. 2019. View Article : Google Scholar : PubMed/NCBI

161 

Wang L, Yi J, Lu LY, Zhang YY, Wang L, Hu GS, Liu YC, Ding JC, Shen HF, Zhao FQ, et al: Estrogen-induced circRNA, circPGR, functions as a ceRNA to promote estrogen receptor-positive breast cancer cell growth by regulating cell cycle-related genes. Theranostics. 11:1732–1752. 2021. View Article : Google Scholar : PubMed/NCBI

162 

Wang S, Qian L, Cao T, Xu L, Jin Y, Hu H, Fu Q, Li Q, Wang Y, Wang J, et al: Advances in the study of CircRNAs in tumor drug resistance. Front Oncol. 12:8683632022. View Article : Google Scholar : PubMed/NCBI

163 

Li C, Zhang J, Yang X, Hu C, Chu T, Zhong R, Shen Y, Hu F, Pan F, Xu J, et al: hsa_circ_0003222 accelerates stemness and progression of non-small cell lung cancer by sponging miR-527. Cell Death Dis. 12:8072021. View Article : Google Scholar : PubMed/NCBI

164 

Feinberg AP: The key role of epigenetics in human disease prevention and mitigation. N Engl J Med. 378:1323–1334. 2018. View Article : Google Scholar : PubMed/NCBI

165 

Srivastava R and Lodhi N: DNA methylation malleability and dysregulation in cancer progression: Understanding the role of PARP1. Biomolecules. 12:4172022. View Article : Google Scholar : PubMed/NCBI

166 

Emran AA, Chatterjee A, Rodger EJ, Tiffen JC, Gallagher SJ, Eccles MR and Hersey P: Targeting DNA methylation and EZH2 activity to overcome melanoma resistance to immunotherapy. Trends Immunol. 40:328–344. 2019. View Article : Google Scholar : PubMed/NCBI

167 

Lv D, Xing C, Cao L, Zhuo Y, Wu T and Gao N: PD-L1 gene promoter methylation represents a potential diagnostic marker in advanced gastric cancer. Oncol Lett. 19:1223–1234. 2020.PubMed/NCBI

168 

Del Castillo Falconi VM, Torres-Arciga K, Matus-Ortega G, Díaz-Chávez J and Herrera LA: DNA methyltransferases: From evolution to clinical applications. Int J Mol Sci. 23:89942022. View Article : Google Scholar : PubMed/NCBI

169 

Lu X, Li Y, Yang W, Tao M, Dai Y, Xu J and Xu Q: Inhibition of NF-κB is required for oleanolic acid to downregulate PD-L1 by promoting DNA demethylation in gastric cancer cells. J Biochem Mol Toxicol. 35:e226212021. View Article : Google Scholar

170 

Liu J, Liu Y, Meng L, Liu K and Ji B: Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma. Oncol Rep. 38:899–907. 2017. View Article : Google Scholar : PubMed/NCBI

171 

Chatterjee A, Rodger EJ, Ahn A, Stockwell PA, Parry M, Motwani J, Gallagher SJ, Shklovskaya E, Tiffen J, Eccles MR and Hersey P: Marked global DNA hypomethylation is associated with constitutive PD-L1 expression in melanoma. iScience. 4:312–325. 2018. View Article : Google Scholar : PubMed/NCBI

172 

Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, et al: Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 527:249–253. 2015. View Article : Google Scholar : PubMed/NCBI

173 

Li X, Wang Z, Huang J, Luo H, Zhu S, Yi H, Zheng L, Hu B, Yu L, Li L, et al: Specific zinc finger-induced methylation of PD-L1 promoter inhibits its expression. FEBS Open Bio. 9:1063–1070. 2019. View Article : Google Scholar : PubMed/NCBI

174 

Garg M: Epithelial-mesenchymal transition-activating transcription factors-multifunctional regulators in cancer. World J Stem Cells. 5:188–195. 2013. View Article : Google Scholar : PubMed/NCBI

175 

Asgarova A, Asgarov K, Godet Y, Peixoto P, Nadaradjane A, Boyer-Guittaut M, Galaine J, Guenat D, Mougey V, Perrard J, et al: PD-L1 expression is regulated by both DNA methylation and NF-kB during EMT signaling in non-small cell lung carcinoma. Oncoimmunology. 7:e14231702018. View Article : Google Scholar : PubMed/NCBI

176 

Zhang Y, Xiang C, Wang Y, Duan Y, Liu C and Zhang Y: PD-L1 promoter methylation mediates the resistance response to anti-PD-1 therapy in NSCLC patients with EGFR-TKI resistance. Oncotarget. 8:101535–101544. 2017. View Article : Google Scholar : PubMed/NCBI

177 

Lai Q, Wang H, Li A, Xu Y, Tang L, Chen Q, Zhang C, Gao Y, Song J and Du Z: Decitibine improve the efficiency of anti-PD-1 therapy via activating the response to IFN/PD-L1 signal of lung cancer cells. Oncogene. 37:2302–2312. 2018. View Article : Google Scholar : PubMed/NCBI

178 

Mu L, Long Y, Yang C, Jin L, Tao H, Ge H, Chang YE, Karachi A, Kubilis PS, De Leon G, et al: The IDH1 mutation-induced oncometabolite, 2-hydroxyglutarate, may affect DNA methylation and expression of PD-L1 in gliomas. Front Mol Neurosci. 11:822018. View Article : Google Scholar : PubMed/NCBI

179 

Briand J, Nadaradjane A, Bougras-Cartron G, Olivier C, Vallette FM and Cartron PF: Diuron exposure and Akt overexpression promote glioma formation through DNA hypomethylation. Clin Epigenetics. 11:1592019. View Article : Google Scholar : PubMed/NCBI

180 

Elashi AA, Sasidharan Nair V, Taha RZ, Shaath H and Elkord E: DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients. Oncoimmunology. 8:e15429182018. View Article : Google Scholar

181 

Jacot W, Lopez-Crapez E, Mollevi C, Boissière-Michot F, Simony-Lafontaine J, Ho-Pun-Cheung A, Chartron E, Theillet C, Lemoine A, Saffroy R, et al: BRCA1 promoter hypermethylation is associated with good prognosis and chemosensitivity in triple-negative breast cancer. Cancers (Basel). 12:8282020. View Article : Google Scholar

182 

Yamada R, Yamaguchi T, Iijima T, Wakaume R, Takao M, Koizumi K, Hishima T and Horiguchi SI: Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer. Int J Clin Oncol. 23:504–513. 2018. View Article : Google Scholar : PubMed/NCBI

183 

Hua S, Gu M, Wang Y, Ban D and Ji H: Oxymatrine reduces expression of programmed death-ligand 1 by promoting DNA demethylation in colorectal cancer cells. Clin Transl Oncol. 23:750–756. 2021. View Article : Google Scholar

184 

Liu Z, Ren Y, Weng S, Xu H, Li L and Han X: A new trend in cancer treatment: The combination of epigenetics and immunotherapy. Front Immunol. 13:8097612022. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

November-2022
Volume 61 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Ma X, Wu J, Wang B, Liu C, Liu L and Sun C: Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review). Int J Oncol 61: 134, 2022.
APA
Ma, X., Wu, J., Wang, B., Liu, C., Liu, L., & Sun, C. (2022). Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review). International Journal of Oncology, 61, 134. https://doi.org/10.3892/ijo.2022.5424
MLA
Ma, X., Wu, J., Wang, B., Liu, C., Liu, L., Sun, C."Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)". International Journal of Oncology 61.5 (2022): 134.
Chicago
Ma, X., Wu, J., Wang, B., Liu, C., Liu, L., Sun, C."Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)". International Journal of Oncology 61, no. 5 (2022): 134. https://doi.org/10.3892/ijo.2022.5424