Open Access

Role and mechanism of programmed death‑ligand 1 in hypoxia‑induced liver cancer immune escape (Review)

  • Authors:
    • Qingxian Wen
    • Tao Han
    • Zijian Wang
    • Shulong Jiang
  • View Affiliations

  • Published online on: February 5, 2020     https://doi.org/10.3892/ol.2020.11369
  • Pages: 2595-2601
  • Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Immune escape plays a vital role in the development of liver cancer. The interaction between programmed death‑ligand 1 (PD‑L1) and programmed cell death‑1 is a key mediator of cancer immune escape, which leads to the suppression of anticancer immunity and promotion of tumor progression. Hypoxia is a common phenomenon in the tumor microenvironment. Under hypoxic conditions, suppressive immune cells, such as regulatory T cells, myeloid‑derived suppressor cells and M2 macrophages, are frequently recruited to tumor tissues to form the immunosuppressive microenvironment in liver cancer. These cells secrete cancer‑promoting inflammatory cytokines, which activate the STAT3 and NF‑κB signaling pathways. Recent studies have shown that STAT3 is associated with NF‑κB and that these transcription factors are often co‑activated to regulate tumor proliferation, survival, angiogenesis and invasion. The activation of STAT3 and NF‑κB signaling pathways can directly and indirectly induce PD‑L1 expression. Therefore, further understanding of the association between hypoxia and PD‑L1 may help in the future treatment of liver cancer. The present review summarizes the recent progresses on PD‑L1‑mediated regulation and facilitation of liver cancer cell immune escape in response to hypoxia.

Introduction

Hepatocellular carcinoma (HCC) is one of the most malignant tumors that pose a severe threat to human health. The latest cancer statistics showed that the number of new liver cancer cases and liver cancer-associated deaths worldwide in 2018 was 841,000 and 782,000, respectively (1). Liver cancer ranked sixth in terms of new cancer cases and fourth in terms of cancer-associated deaths worldwide in 2018 (1). The available evidence indicates that immune escape of liver cancer cells plays a vital role in the development of this malignancy (2,3) and impairs the effectiveness of antitumor treatment (4). Therefore, effective blockage of the occurrence of immune escape has become the focus of attention in the prevention and treatment of HCC.

It is now known that the activation or inhibition of immune cells in the body is regulated by positive and negative signals (5,6). Among them, the interaction between programmed cell death-1 (PD-1, also termed CD279) and programmed death-ligand 1 (PD-L1, also termed CD274 and B7-H1) is the primary negative immune regulatory signal, which inhibits the antitumor immune activity of effector cells and mediates tumor immune escape (710). Furthermore, immune checkpoint blockers have recently emerged as a mainstream strategy for the treatment of multiple solid tumors, including liver cancer (1114).

Hypoxia, a common phenomenon in the tumor microenvironment, induces the expression of PD-L1 to promote immune escape (1517). A number of immune cells with immunosuppressive activities, including tumor-associated regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), are recruited to the tumor tissue to form an immunosuppressive microenvironment (1820). Moreover, under hypoxic conditions, the expression of PD-L1 is rapidly upregulated in these immunosuppressive cells in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner (21,22). In this regard, the comprehensive analysis of the role and mechanism of PD-L1 in hypoxia-induced immune escape is essential for the improved treatment of liver cancer. The present review summarizes the recent findings regarding the regulation of PD-L1-mediated hypoxia-induced immune escape in HCC cells and discusses the underlying mechanisms.

PD-L1/PD-1 interaction in the immune escape of liver cancer

The compromised immune status of the body is associated with the occurrence of liver cancer. When the immune function is weakened or suppressed, the incidence of liver cancer will increase significantly. Normally, once liver cancer cells are formed in the body, the immune system can inhibit or kill these cells in a variety of ways (2325). However, despite the immune surveillance and scavenger receptors, it remains challenging to curb the occurrence and development of liver cancer (26). The main reason is that liver cancer cells may escape from the immune system attack through various mechanisms. The PD-L1/PD-1 pathway, which promotes cancer cell survival and proliferation, is a key mediator of the immune escape of HCC cells (2729).

Previous studies have shown that T cell-mediated cellular immunity plays a pivotal role in the recognition and killing of tumor cells (30,31). T cells recognize major histocompatibility complexes that bear antigens derived from the surface of cancer cells, which allows subsequent tumor recognition and targeted killing (32). Recently, it has been demonstrated that various mechanisms play a role in increasing the expression of PD-L1 in tumor cells and in the tumor microenvironment. PD-L1 is a transmembrane glycoprotein composed of 290 amino acids, which belongs to the B7 family of immune-regulatory ligands. The binding of PD-L1 to its PD-1 receptor suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumor cell killing, leading to the occurrence of tumor cell immune escape (33). In the healthy immune system, the PD-L1/PD-1 pathway plays a critical role in maintaining the balance between protective immunity and immune tolerance. However, aberrant activation of the PD-L1/PD-1 signaling pathway in the tumor microenvironment is associated with the development of liver cancer. A multivariate analysis showed that PD-L1 expression is an independent predictor of postoperative recurrence of HCC (7,34).

Accumulating evidence has revealed that the elevated level of PD-L1 in the tumor microenvironment constrains antitumor immunity via the inhibition of antitumor effector cell function and enhancement of the inhibitory activity of immunosuppressive cells (12,16,35,36). Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are the main local antitumor immune effector cells. Activated CTLs are marked by granzyme B, which is the primary molecular mediator of apoptosis (37). It has been shown that the activation of the PD-1/PD-L1 signaling pathway restrains CTL function by inducing apoptosis, anergy and exhaustion, and promoting the secretion of immunosuppressive factors, leading to the immune escape of tumor cells (38). Hepatoma tumor-infiltrating CTLs express PD-1 molecules, which bind to PD-L1 that are expressed on the surface of tumor cells, resulting in the depletion and apoptosis of CTLs (39).

There are a large number of active immunosuppressive cells in the tumor microenvironment, including Tregs, MDSCs and TAMs (40). These immune cells form a complex multi-cell population, which is an important part of the tumor microenvironment. Indeed, various molecular interactions between immune and cancer cells are considered a crucial step in the direct or indirect induction of the occurrence and development of tumors. These immunosuppressive cells also express a large number of PD-L1 molecules, which induce apoptosis in CTLs by binding to PD-1 (41). Tregs, characterized by the expression of CD4, CD25 and Forkhead box protein P3 (FOXP3), are the most characteristic immunosuppressive cells. The inhibition of the immune response by Tregs is also mediated by cell contact or the secretion of inhibitory cytokines, such as interleukin (IL)-10 and transforming growth factor-β (TGF-β) (42). A previous study found that PD-L1 promoted Treg differentiation by converting CD4+CD25+FOXP3 T cells to CD4+CD25+FOXP3+ Tregs. Furthermore, higher expression levels of PD-L1 on hepatic dendritic cells were associated with an increased Treg cell induction (43). Specific blocking of PD-L1 by small interfering (si)RNA or monoclonal antibodies decreased the production of CD4+CD25+FOXP3+ Tregs and induced Treg apoptosis (44). In a pig xenograft model, PD-L1 was found to enhance Treg function and stimulate IL-10 production, thereby further promoting the immune inhibitory function (45). Clinical data also showed that PD-L1 effectively stimulated the secretion of IL-10 in patients with liver cancer, thereby further enhancing the immunosuppressive effect of Tregs (46). Collectively, these studies have shown that the PD-L1/PD-1 pathway inhibits the antitumor function of CTLs, enhances the immunosuppressive activity of Tregs, and promotes the secretion of immunosuppressive factors by transmitting inhibitory signals, leading to the occurrence of tumor immune escape.

Hypoxia-induced recruitment of immunosuppressive cells and regulation of PD-L1 expression

Hypoxia is a common phenomenon in the tumor microenvironment (4749). Previous studies have revealed that tumor hypoxia alters the composition and activity of tumor-associated immune cells, and that numerous immune cells with immunosuppressive activities are recruited to tumor tissues to form the immunosuppressive microenvironment (18,50,51). Under hypoxic conditions, tumor cells and macrophages secrete a variety of cytokines and chemokines, including C-C motif chemokine (CCL)22, CCL28 and IL-10, which results in the recruitment of CD4+CD25+FOXP3+ Tregs from peripheral blood to inhibit T cell-mediated antitumor responses (18,52,53). Hypoxia also promotes the recruitment of MDSCs (19). MDSCs are a group of undifferentiated, immunosuppressive, bone marrow-derived heterogeneous cell populations, which have a strong immunosuppressive function (54). MDSCs expressing arginase-1, which mediate the depletion of L-arginine, impede T cell proliferation, and are associated with the downregulation of T cell receptor (TCR) subunit CD3ζ, resulting in decreased TCR response (5557). The occurrence of a tumor in the liver results in increased levels of MDSCs at the tumor site, and the activation of the MyD88-NF-κB pathway stimulates the secretion of IL-10 to inhibit the expression of IL-12 in dendritic cells and the activation of T cells (58). MDSCs also induce NK cell inactivation through TGF-β and the NK receptor p30 on the cell surface (59). Furthermore, a previous study indicated that MDSCs inhibit immune response and promote the development of liver cancer by inducing the generation of CD4+CD25+FOXP3+ Tregs (60). In addition, the tumor hypoxia microenvironment directly induces macrophage M2 polarization, angiogenesis, and tumor growth and metastasis (20). M2 type macrophages inhibit the antitumor immune response by producing TGF-β and IL-10, and their numbers in the tumor microenvironment are negatively correlated with the prognosis of liver cancer patients (61,62). M2 microphages also secrete a range of specific chemokines, including CCL17, CCL22 and CCL24, which recruit regulatory T cells to tumor sites (62). As a result, Tregs, MDSCs and M2 macrophages have potent immunosuppressive activities and together promote the occurrence of tumor immune escape (Fig. 1).

Under hypoxic conditions, HIF-1α is a crucial transcription factor that mediates the effect of hypoxia on the adaptive regulation of tumor cells and the tumor microenvironment (6365). Under normoxic conditions, HIF-1α is hydroxylated by prolyl hydroxylase (PHD) and ubiquitinated/degraded by the von Hippel-Lindau E3 ubiquitin ligase complex. Under hypoxic conditions, PHD activity is inhibited, and HIF-1α ubiquitination and degradation are decreased, thereby stabilizing HIF-1α (66). Previous studies have shown that HIF-1α is associated with PD-L1 expression (15,22). Under hypoxic conditions, tumor cells, myeloid suppressor cells, macrophages and dendritic cells all undergo rapid upregulation of PD-L1 in a HIF-1α-dependent manner. Chromatin immunoprecipitation and luciferase reporter assays showed that HIF-1α induced the expression of PD-L1 by directly binding to the hypoxia response element region of the PD-L1 promoter. Furthermore, the inhibition of PD-L1 expression significantly decreased the secretion of IL-6 and IL-10 by MDSC, leading to the activation of T cells (22). Another in vitro study also revealed that hypoxia stimulated the expression of PD-L1 in a variety of human and murine tumor cells through HIF-1α (15). These studies demonstrate that hypoxia induces PD-L1 expression by activating the HIF-1α cascade.

Involvement of STAT3 and NF-κB in the regulation of PD-L1 expression in liver cancer

Accumulating evidence has indicated that the essential mechanism underlying tumor immune escape is associated with the presence of a large number of cytokines and growth factors with immunosuppressive activities in the tumor microenvironment, such as IL-6, vascular endothelial growth factor, TGF-β, IL-10, IL-13, macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (6769). These cytokines stimulate immune inhibitory cells, including Tregs, TAMs and MDSCs, and mediate the expression of a series of genes by activating various signaling pathways. Among them, the STAT3 and NF-κB pathways are essential hubs linking these cytokines to cellular responses (7073).

STAT3 is a member of the STAT family of transcription factors. When cytokines in the tumor microenvironment bind to their receptors, the Janus kinase and/or proto-oncogene tyrosine-protein kinase Src will be activated and able to phosphorylate STAT3. Following dimerization and nuclear translocation, STAT3 will initiate the transcription of downstream genes. A previous study found that STAT3 activation in tumor cells induces the secretion of IL-6 and IL-10 cytokines, which results in Treg proliferation. Moreover, STAT3 is also activated in Tregs and further stimulates the expression of FOXP3, TGF-β and IL-10, which inhibits CTLs and promotes the formation of an immunosuppressive environment (70,74,75).

In addition, STAT3 and NF-κB are often coactivated in tumor cells and play a vital role in the regulation of the expression of cancer-promoting inflammatory genes (76). The coordination between STAT3 and NF-κB is mainly manifested in the following aspects: i) Multiple inflammatory factors, especially IL-6, induced by NF-κB are essential activators of STAT3; ii) STAT3 directly interacts with the NF-κB family member transcription factor p65 (RelA), leading to its acetylation and inhibition of nuclear export, and constitutive activation of NF-κB; iii) STAT3 and NF-κB co-regulate the expression of a number of oncogenes and inflammatory genes; and iv) the inflammatory factors induced by NF-κB and STAT3 form a positive feedback loop to further activate NF-κB and STAT3 (77,78).

Notably, it has been shown that the expression of HIF-1α is regulated by both NF-κB and STAT3. Under hypoxic conditions, STAT3 is activated by phosphorylation, which not only blocks HIF-1α degradation but also increases the synthesis of HIF-1α (79). In human breast cancer MCF-7 cells, the depletion of STAT3 by siRNA inhibited CoCl2-induced HIF-1α nuclear accumulation (80). The NF-κB signaling pathway is also activated under hypoxic conditions (81). Gel shift assay and chromatin immunoprecipitation experiments confirmed that the NF-κB subunits p50 and RelA bind to the promoter of HIF-1α and activate its transcription (82). Since HIF-1α transcriptionally induces PD-L1, these studies indicate that the activation of the STAT3 and NF-κB pathways may indirectly stimulate PD-L1 expression under hypoxic conditions.

Furthermore, several studies have shown that the STAT3 and NF-κB signaling pathways are also involved in the direct regulation of PD-L1 at the transcriptional level (8386). It has been demonstrated that the co-culture of liver cancer cells (BEL-7402 and SMMC-7721) with macrophages resulted in increased PD-L1 mRNA and protein levels and that blocking either the NF-κB or the STAT3 signaling pathway inhibited this co-culture effect on PD-L1 expression (83). Another study showed that EB virus latent membrane protein 1 (LMP1) induced the expression of PD-L1 by the activation of NF-κB or STAT3; the inhibition of one of these pathways notably decreased LMP1-stimulated PD-L1 expression (84). Chromatin immunoprecipitation and reporter assays revealed direct binding of STAT-3 and NF-κB to the PD-L1 promoter, triggering PD-L1 transcription (85,86). These studies indicate that the STAT3/NF-κB pathways directly and indirectly regulate PD-L1 expression in the hypoxic microenvironment (Fig. 2).

Relevance for clinical practice

Immunotherapy is emerging as an appealing and attractive strategy for the treatment of HCC. Novel immune checkpoint inhibitors have revolutionized pharmacological treatment options for cancer with remarkable clinical outcomes in a number of human malignancies, including advanced HCC. It has been shown that the inhibition of PD-L1 improves overall survival rates in patients with HCC (87). Moreover, since HIF-1α plays a vital role in regulating immune escape in the hypoxic tumor microenvironment, a HIF-1α inhibitor is being investigated for the treatment of HCC (8891). Several inhibitors of STAT3 and/or NF-κB are undergoing clinical trials for HCC (92,93). In addition, due to the upregulation of PD-L1 by STAT3, NF-κB and HIF-1α, a combination of a PD-L1 antibody with small molecule inhibitors of STAT3, NF-κB or HIF-1α could be a more effective therapeutic strategy in advanced liver cancer.

Conclusions

Immune escape is a key cause of tumor development. Enhancing antitumor immunity of the body, as the core treatment strategy, is being extensively studied in cancer care and research. In the tumor hypoxic microenvironment, PD-L1 overexpression is a crucial factor contributing to liver cancer immune escape and is associated with the activation of the STAT3/NF-κB pathway and HIF-1α. Therefore, the inhibition of STAT3 and NF-κB pathways or HIF-1α should decrease PD-L1 expression and reverse immune escape. Agents blocking STAT3, NF-κB or HIF-1α have great potential for cancer immunotherapy, particularly in patients developing resistance to PD-L1 and PD1 inhibitors.

Acknowledgements

Not applicable.

Funding

This work was supported in part by the National Natural Science Foundation of China (grant no. 81873249), the Young Taishan Scholars Program of Shandong Province (grant no. tsqn201909200) and the Natural Science Foundation of Shandong Province (grant. no. ZR2019MH058).

Availability of data and materials

Not applicable.

Authors' contributions

SJ contributed to the conception of the study. QW wrote the manuscript with support from SJ, TH and ZW. All authors have read and approved the final version of the manuscript.

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.

References

1 

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI

2 

Han C, Jiang Y, Wang Z and Wang H: Natural killer cells involved in tumour immune escape of hepatocellular carcinomar. Int Immunopharmacol. 73:10–16. 2019. View Article : Google Scholar : PubMed/NCBI

3 

Xie Y, Xiang Y, Sheng J, Zhang D, Yao X, Yang Y and Zhang X: Immunotherapy for hepatocellular carcinoma: Current advances and future expectations. J Immunol Res. 2018:87409762018. View Article : Google Scholar : PubMed/NCBI

4 

Harding JJ, El Dika I and Abou-Alfa GK: Immunotherapy in hepatocellular carcinoma: Primed to make a difference? Cancer. 122:367–377. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Najafi M, Farhood B and Mortezaee K: Contribution of regulatory T cells to cancer: A review. J Cell Physiol. 234:7983–7993. 2019. View Article : Google Scholar : PubMed/NCBI

7 

Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 515:563–567. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Shergold AL, Millar R and Nibbs RJB: Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade. Pharmacol Res. 145:1042582019. View Article : Google Scholar : PubMed/NCBI

9 

Pio R, Ajona D, Ortiz-Espinosa S, Mantovani A and Lambris JD: Complementing the cancer-immunity cycle. Front Immunol. 10:7742019. View Article : Google Scholar : PubMed/NCBI

10 

Prestipino A and Zeiser R: Clinical implications of tumor-intrinsic mechanisms regulating PD-L1. Sci Transl Med. 11(pii): eaav48102019. View Article : Google Scholar : PubMed/NCBI

11 

Iñarrairaegui M, Melero I and Sangro B: Immunotherapy of hepatocellular carcinoma: Facts and hopes. Clin Cancer Res. 24:1518–1524. 2018. View Article : Google Scholar : PubMed/NCBI

12 

Hamanishi J, Mandai M, Matsumura N, Abiko K, Baba T and Konishi I: PD-1/PD-L1 blockade in cancer treatment: Perspectives and issues. Int J Clin Oncol. 21:462–473. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Mocan T, Sparchez Z, Craciun R, Bora CN and Leucuta DC: Programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) axis in hepatocellular carcinoma: Prognostic and therapeutic perspectives. Clin Transl Oncol. 21:702–712. 2019. View Article : Google Scholar : PubMed/NCBI

14 

Ho CM, Chen HL, Hu RH and Lee PH: Harnessing immunotherapy for liver recipients with hepatocellular carcinoma: A review from a transplant oncology perspective. Ther Adv Med Oncol. 11:17588359198434632019. View Article : Google Scholar : PubMed/NCBI

15 

Barsoum IB, Smallwood CA, Siemens DR and Graham CH: A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 74:665–674. 2014. View Article : Google Scholar : PubMed/NCBI

16 

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 : PubMed/NCBI

17 

Guo R, Li Y, Wang Z, Bai H, Duan J, Wang S, Wang L and Wang J: Hypoxia-inducible factor-1α and nuclear factor-κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non-small-cell lung cancer cells. Cancer Sci. 110:1665–1675. 2019. View Article : Google Scholar : PubMed/NCBI

18 

Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, Gimotty PA, Gilks CB, Lal P, Zhang L and Coukos G: Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 475:226–230. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Terry S, Buart S and Chouaib S: Hypoxic stress-induced tumor and immune plasticity, suppression, and impact on tumor heterogeneity. Front Immunol. 8:16252017. View Article : Google Scholar : PubMed/NCBI

20 

Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, Movahedi K, Houbracken I, Schouppe E, Elkrim Y, et al: Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res. 74:24–30. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Labiano S, Palazon A and Melero I: Immune response regulation in the tumor microenvironment by hypoxia. Semin Oncol. 42:378–386. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V and Chouaib S: PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 211:781–790. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Reig M, Boix L, Mariño Z, Torres F, Forns X and Bruix J: Liver cancer emergence associated with antiviral treatment: An immune surveillance failure? Semin Liver Dis. 37:109–118. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, Schemmer P, Bruns H, Eiermann T, Price DA, et al: Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology. 59:1415–1426. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Schreiber RD, Old LJ and Smyth MJ: Cancer immunoediting: Integrating immunity's roles in cancer suppression and promotion. Science. 331:1565–1570. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Owusu Sekyere S, Schlevogt B, Mettke F, Kabbani M, Deterding K, Wirth TC, Vogel A, Manns MP, Falk CS, Cornberg M, et al: HCC Immune surveillance and antiviral therapy of hepatitis C virus infection. Liver Cancer. 8:41–65. 2019. View Article : Google Scholar : PubMed/NCBI

27 

Kudo M: Systemic therapy for hepatocellular carcinoma: Latest advances. Cancers (Basel). 10(pii): E4122018. View Article : Google Scholar : PubMed/NCBI

28 

Sahin B: Enlighting the shadow for advanced hepatocellular carcinoma: Immunotherapy with immune checkpoint inhibitors. J Gastrointest Cancer. 48:288–290. 2017. View Article : Google Scholar : PubMed/NCBI

29 

Waidmann O: Recent developments with immunotherapy for hepatocellular carcinoma. Expert Opin Biol Ther. 18:905–910. 2018. View Article : Google Scholar : PubMed/NCBI

30 

Farhood B, Najafi M and Mortezaee K: CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. J Cell Physiol. 234:8509–8521. 2019. View Article : Google Scholar : PubMed/NCBI

31 

Kosti P, Maher J and Arnold JN: Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors. Front Immunol. 9:11042018. View Article : Google Scholar : PubMed/NCBI

32 

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

33 

Chen Y, Wang Q, Shi B, Xu P, Hu Z, Bai L and Zhang X: Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines. Cytokine. 56:231–238. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, et al: Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 15:971–979. 2009. View Article : Google Scholar : PubMed/NCBI

35 

Lian S, Xie R, Ye Y, Xie X, Li S, Lu Y, Li B, Cheng Y, Katanaev VL and Jia L: Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release. EBioMedicine. 42:281–295. 2019. View Article : Google Scholar : PubMed/NCBI

36 

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

37 

Barry M, Heibein JA, Pinkoski MJ, Lee SF, Moyer RW, Green DR and Bleackley RC: Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid. Mol Cell Biol. 20:3781–3794. 2000. View Article : Google Scholar : PubMed/NCBI

38 

Sanmamed MF and Chen L: Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J. 20:256–261. 2014. View Article : Google Scholar : PubMed/NCBI

39 

Zhao Q, Xiao X, Wu Y, Wei Y, Zhu LY, Zhou J and Kuang DM: Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. Eur J Immunol. 41:2314–2322. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Andersen MH: The balance players of the adaptive immune system. Cancer Res. 78:1379–1382. 2018. View Article : Google Scholar : PubMed/NCBI

41 

Galdiero MR, Garlanda C, Jaillon S, Marone G and Mantovani A: Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol. 228:1404–1412. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Campbell DJ and Koch MA: Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol. 11:119–130. 2011. View Article : Google Scholar : PubMed/NCBI

43 

Liu H, Bakthavatsalam R, Meng Z, Li Z, Li W, Perkins JD and Reyes J: PD-L1 signal on liver dendritic cells is critical for Foxp3(+)CD4(+)CD25(+) Treg and liver tolerance induction in mice. Transplant Proc. 45:1853–1855. 2013. View Article : Google Scholar : PubMed/NCBI

44 

Beswick EJ, Pinchuk IV, Das S, Powell DW and Reyes VE: Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun. 75:4334–4341. 2007. View Article : Google Scholar : PubMed/NCBI

45 

Ding Q, Lu L, Zhou X, Zhou Y and Chou KY: Human PD-L1-overexpressing porcine vascular endothelial cells induce functionally suppressive human CD4+CD25hiFoxp3+ Treg cells. J Leukoc Biol. 90:77–86. 2011. View Article : Google Scholar : PubMed/NCBI

46 

Geng L, Deng J, Jiang G, Song P, Wang Z, Jiang Z, Zhang M and Zheng S: B7-H1 up-regulated expression in human hepatocellular carcinoma tissue: Correlation with tumor interleukin-10 levels. Hepatogastroenterology. 58:960–964. 2011.PubMed/NCBI

47 

Sormendi S and Wielockx B: Hypoxia pathway proteins as central mediators of metabolism in the tumor cells and their microenvironment. Front Immunol. 9:402018. View Article : Google Scholar : PubMed/NCBI

48 

Deng J, Li J, Sarde A, Lines JL, Lee YC, Qian DC, Pechenick DA, Manivanh R, Le Mercier I, Lowrey CH, et al: Hypoxia-induced VISTA promotes the suppressive function of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Immunol Res. 7:1079–1090. 2019. View Article : Google Scholar : PubMed/NCBI

49 

Hayashi Y, Yokota A, Harada H and Huang G: Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer. Cancer Sci. 110:1510–1517. 2019. View Article : Google Scholar : PubMed/NCBI

50 

Chouaib S, Umansky V and Kieda C: The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment. Contemp Oncol (Pozn). 22:7–13. 2018.PubMed/NCBI

51 

Guo X, Xue H, Shao Q, Wang J, Guo X, Chen X, Zhang J, Xu S, Li T, Zhang P, et al: Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR. Oncotarget. 7:80521–80542. 2016. View Article : Google Scholar : PubMed/NCBI

52 

Vaupel P and Multhoff G: Hypoxia-/HIF-1α-driven factors of the tumor microenvironment impeding antitumor immune responses and promoting malignant progression. Adv Exp Med Biol. 1072:171–175. 2018. View Article : Google Scholar : PubMed/NCBI

53 

Kumar V and Gabrilovich DI: Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology. 143:512–519. 2014. View Article : Google Scholar : PubMed/NCBI

54 

Gabrilovich DI and Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 9:162–174. 2009. View Article : Google Scholar : PubMed/NCBI

55 

Rodriguez PC, Ochoa AC and Al-Khami AA: Arginine metabolism in myeloid cells shapes innate and adaptive immunity. Front Immunol. 8:932017. View Article : Google Scholar : PubMed/NCBI

56 

Munder M, Choi BS, Rogers M and Kropf P: L-arginine deprivation impairs Leishmania major-specific T-cell responses. Eur J Immunol. 39:2161–2172. 2009. View Article : Google Scholar : PubMed/NCBI

57 

Bronte V and Zanovello P: Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 5:641–654. 2005. View Article : Google Scholar : PubMed/NCBI

58 

Hu CE, Gan J, Zhang RD, Cheng YR and Huang GJ: Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand J Gastroenterol. 46:156–164. 2011. View Article : Google Scholar : PubMed/NCBI

59 

Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF and Korangy F: Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology. 50:799–807. 2009. View Article : Google Scholar : PubMed/NCBI

60 

Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, Greten TF and Korangy F: A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 135:234–243. 2008. View Article : Google Scholar : PubMed/NCBI

61 

Amann T, Bataille F, Spruss T, Mühlbauer M, Gäbele E, Schölmerich J, Kiefer P, Bosserhoff AK and Hellerbrand C: Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma. Cancer Sci. 100:646–653. 2009. View Article : Google Scholar : PubMed/NCBI

62 

Ju MJ, Qiu SJ, Fan J, Xiao YS, Gao Q, Zhou J, Li YW and Tang ZY: Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection. Am J Clin Pathol. 131:498–510. 2009. View Article : Google Scholar : PubMed/NCBI

63 

Soni S and Padwad YS: HIF-1 in cancer therapy: Two decade long story of a transcription factor. Acta Oncol. 56:503–515. 2017. View Article : Google Scholar : PubMed/NCBI

64 

Xia Y, Jiang L and Zhong T: The role of HIF-1α in chemo-/radioresistant tumors. Onco Targets Ther. 11:3003–3011. 2018. View Article : Google Scholar : PubMed/NCBI

65 

Petrova V, Annicchiarico-Petruzzelli M, Melino G and Amelio I: The hypoxic tumour microenvironment. Oncogenesis. 7:102018. View Article : Google Scholar : PubMed/NCBI

66 

Günter J, Ruiz-Serrano A, Pickel C, Wenger RH and Scholz CC: The functional interplay between the HIF pathway and the ubiquitin system-more than a one-way road. Exp Cell Res. 356:152–159. 2017. View Article : Google Scholar : PubMed/NCBI

67 

Rabinovich GA, Gabrilovich D and Sotomayor EM: Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 25:267–296. 2007. View Article : Google Scholar : PubMed/NCBI

68 

Bian X, Xiao YT, Wu T, Yao M, Du L, Ren S and Wang J: Microvesicles and chemokines in tumor microenvironment: Mediators of intercellular communications in tumor progression. Mol Cancer. 18:502019. View Article : Google Scholar : PubMed/NCBI

69 

Gun SY, Lee SWL, Sieow JL and Wong SC: Targeting immune cells for cancer therapy. Redox Biol. 25:1011742019. View Article : Google Scholar : PubMed/NCBI

70 

Wang Y, Shen Y, Wang S, Shen Q and Zhou X: The role of STAT3 in leading the crosstalk between human cancers and the immune system. Cancer Lett. 415:117–128. 2018. View Article : Google Scholar : PubMed/NCBI

71 

Huynh J, Chand A, Gough D and Ernst M: Therapeutically exploiting STAT3 activity in cancer-using tissue repair as a road map. Nat Rev Cancer. 19:82–96. 2019. View Article : Google Scholar : PubMed/NCBI

72 

Loh CY, Arya A, Naema AF, Wong WF, Sethi G and Looi CY: Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: Functions and therapeutic implication. Front Oncol. 9:482019. View Article : Google Scholar : PubMed/NCBI

73 

Capece D, Verzella D, Tessitore A, Alesse E, Capalbo C and Zazzeroni F: Cancer secretome and inflammation: The bright and the dark sides of NF-κB. Semin Cell Dev Biol. 78:51–61. 2018. View Article : Google Scholar : PubMed/NCBI

74 

Yu H, Kortylewski M and Pardoll D: Crosstalk between cancer and immune cells: Role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 7:41–51. 2007. View Article : Google Scholar : PubMed/NCBI

75 

Kitamura H, Ohno Y, Toyoshima Y, Ohtake J, Homma S, Kawamura H, Takahashi N and Taketomi A: Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy. Cancer Sci. 108:1947–1952. 2017. View Article : Google Scholar : PubMed/NCBI

76 

Kunnumakkara AB, Sailo BL, Banik K, Harsha C, Prasad S, Gupta SC, Bharti AC and Aggarwal BB: Chronic diseases, inflammation, and spices: How are they linked? J Transl Med. 16:142018. View Article : Google Scholar : PubMed/NCBI

77 

Yu H, Pardoll D and Jove R: STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer. 9:798–809. 2009. View Article : Google Scholar : PubMed/NCBI

78 

Fan Y, Mao R and Yang J: NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell. 4:176–185. 2013. View Article : Google Scholar : PubMed/NCBI

79 

Gao P, Niu N, Wei T, Tozawa H, Chen X, Zhang C, Zhang J, Wada Y, Kapron CM and Liu J: The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis. Oncotarget. 8:69139–69161. 2017.PubMed/NCBI

80 

Cascio S, D'Andrea A, Ferla R, Surmacz E, Gulotta E, Amodeo V, Bazan V, Gebbia N and Russo A: miR-20b modulates VEGF expression by targeting HIF-1 alpha and STAT3 in MCF-7 breast cancer cells. J Cell Physiol. 224:242–249. 2010.PubMed/NCBI

81 

Van Welden S, Selfridge AC and Hindryckx P: Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol. 14:596–611. 2017. View Article : Google Scholar : PubMed/NCBI

82 

Belaiba RS, Bonello S, Zahringer C, Schmidt S, Hess J, Kietzmann T and Gorlach A: Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells. Mol Biol Cell. 18:4691–4697. 2007. View Article : Google Scholar : PubMed/NCBI

83 

Chen J, Li G, Meng H, Fan Y, Song Y, Wang S, Zhu F, Guo C, Zhang L and Shi Y: Upregulation of B7-H1 expression is associated with macrophage infiltration in hepatocellular carcinomas. Cancer Immunol Immunother. 61:101–108. 2012. View Article : Google Scholar : PubMed/NCBI

84 

Fang W, Zhang J, Hong S, Zhan J, Chen N, Qin T, Tang Y, Zhang Y, Kang S, Zhou T, et al: EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy. Oncotarget. 5:12189–12202. 2014. View Article : Google Scholar : PubMed/NCBI

85 

Wölfle SJ, Strebovsky J, Bartz H, Sähr A, Arnold C, Kaiser C, Dalpke AH and Heeg K: PD-L1 expression on tolerogenic APCs is controlled by STAT-3. Eur J Immunol. 41:413–424. 2011. View Article : Google Scholar : PubMed/NCBI

86 

Huang G, Wen Q, Zhao Y, Gao Q and Bai Y: NF-κB plays a key role in inducing CD274 expression in human monocytes after lipopolysaccharide treatment. PLoS One. 8:e616022013. View Article : Google Scholar : PubMed/NCBI

87 

Kudo M: Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology. 93 (Suppl 1):S147–S159. 2017. View Article : Google Scholar

88 

Lin D and Wu J: Hypoxia inducible factor in hepatocellular carcinoma: A therapeutic target. World J Gastroenterol. 21:12171–12178. 2015. View Article : Google Scholar : PubMed/NCBI

89 

Wu L, Fu Z, Zhou S, Gong J, Liu CA, Qiao Z and Li S: HIF-1α and HIF-2α: Siblings in promoting angiogenesis of residual hepatocellular carcinoma after high-intensity focused ultrasound ablation. PLoS One. 9:e889132014. View Article : Google Scholar : PubMed/NCBI

90 

Liang Y, Zheng T, Song R, Wang J, Yin D, Wang L, Liu H, Tian L, Fang X, Meng X, et al: Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology. 57:1847–1857. 2013. View Article : Google Scholar : PubMed/NCBI

91 

Liu F, Wang P, Jiang X, Tan G, Qiao H, Jiang H, Krissansen GW and Sun X: Antisense hypoxia-inducible factor 1alpha gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma. Cancer Sci. 99:2055–2061. 2008.PubMed/NCBI

92 

Brambilla L, Genini D, Laurini E, Merulla J, Perez L, Fermeglia M, Carbone GM, Pricl S and Catapano CV: Hitting the right spot: Mechanism of action of OPB-31121, a novel and potent inhibitor of the signal transducer and activator of transcription 3 (STAT3). Mol Oncol. 9:1194–1206. 2015. View Article : Google Scholar : PubMed/NCBI

93 

Ciombor KK, Feng Y, Benson AB III, Su Y, Horton L, Short SP, Kauh JS, Staley C, Mulcahy M, Powell M, et al: Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): A trial of the Eastern Cooperative Oncology Group. Invest New Drugs. 32:1017–1027. 2014. View Article : Google Scholar : PubMed/NCBI

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Spandidos Publications style
Wen Q, Han T, Wang Z and Jiang S: Role and mechanism of programmed death‑ligand 1 in hypoxia‑induced liver cancer immune escape (Review). Oncol Lett 19: 2595-2601, 2020.
APA
Wen, Q., Han, T., Wang, Z., & Jiang, S. (2020). Role and mechanism of programmed death‑ligand 1 in hypoxia‑induced liver cancer immune escape (Review). Oncology Letters, 19, 2595-2601. https://doi.org/10.3892/ol.2020.11369
MLA
Wen, Q., Han, T., Wang, Z., Jiang, S."Role and mechanism of programmed death‑ligand 1 in hypoxia‑induced liver cancer immune escape (Review)". Oncology Letters 19.4 (2020): 2595-2601.
Chicago
Wen, Q., Han, T., Wang, Z., Jiang, S."Role and mechanism of programmed death‑ligand 1 in hypoxia‑induced liver cancer immune escape (Review)". Oncology Letters 19, no. 4 (2020): 2595-2601. https://doi.org/10.3892/ol.2020.11369