T lymphocyte‑related immune response and immunotherapy in gastric cancer (Review)
- Authors:
- Published online on: September 6, 2024 https://doi.org/10.3892/ol.2024.14670
- Article Number: 537
Abstract
Introduction
Gastric cancer (GC) is a global healthcare challenge characterized by significant geographic variability in incidence, treatment strategies and outcomes. The prognosis of advanced GC remains poor, with most patients being diagnosed in South America, China and Europe (1,2). Since the 1990s, several randomized controlled trials have demonstrated that surgical excision combined with chemotherapy, with or without radiation, can lead to improved outcomes in advanced GC (3,4). However, as of 2020, GC was still the fifth most common malignancy and fourth in terms of mortality worldwide, accounting for >1 million new diagnoses and nearly 770,000 deaths (5). The etiology of GC is not fully understood, but smoking, Helicobacter pylori infections, genetic factors and environmental factors are key contributors to its pathogenesis. Enhanced screening and eradication of H. pylori have reduced the incidence of GC (6,7), suggesting that infections and chronic inflammation promote GC development. Inflammation and immunity have become central issues in cancer research (8,9), with immunotherapy emerging as one of the most promising strategies for treating several types of cancer (10,11).
Advances in understanding the molecular biology of GC have led to the exploration of combinations of traditional chemotherapy with newer agents targeting molecular abnormalities (12,13). However, most targeted therapies have proven ineffective (14,15), with the exceptions of trastuzumab for human epidermal growth factor receptor 2-positive patients and ramucirumab for second-line treatment (16–18). Unlike these therapies, which focus on recognizing and killing the tumor itself, immunotherapy aims to utilize the immune system o the host to identify and eradicate cancer cells (19).
Previous research has shown that the immune system not only suppresses cancer growth by killing cancer cells but also influences the tumor microenvironment (TME) and selects cancer cells that are more suited to the host immune system, thus promoting cancer progression (20). Based on the theory of enhancing tumor immunogenicity and boosting the immune response to tumors, multiple immunotherapy strategies have been developed for various cancers (11,21), including GC (22). T cells are crucial mediators of cellular immunity and are pivotal in the tumor immune response.
The present review article summarizes the T lymphocytes in immune response to GC and highlights several promising T lymphocyte-mediated immunotherapy strategies.
T cell-related tumor immune response
Based on their cell surface phenotype, T cells can be divided into CD4+ T cells and CD8+ T cells. CD8+ T cells are commonly called cytotoxic T lymphocytes (CTLs) because of their cytotoxicity (23). CD4+ T cells, also called T helper cells (Th cells), can be classified into Th1, Th2, Th17, regulatory T cells (Tregs) and T follicular helper cells based on their functions and cytokine secretion (24). The T cell-mediated immune response is the main response to tumors and can be described in multiple steps (the cancer-immunity cycle) (25,26). First, tumor-associated antigens (TAAs) are directly presented on the tumor cell surface through the major histocompatibility complex (MHC) class I or are taken up by antigen-presenting cells (APCs) and cross-presented on the cell surface through MHC I, which enables T cells to receive the first signal of activation through T cell receptor (TCR) binding with MHC I (27). Then, APCs provide a co-stimulatory signal as a second signal, and various cytokines provide a third signal (28). Finally, the activated T cells migrate to and infiltrate the tumor (23).
In the past 2 decades, a number of studies have demonstrated that the immune response can not only kill tumors but also lead to tumor cells escaping immunosurveillance (29). This process is defined as ‘cancer immunoediting’ and comprises three phases: Elimination, equilibrium and escape (20). During the elimination phase, before the tumor becomes detectable, the innate and adaptive immune systems collaborate to identify and eliminate tumor cells that escape tumor suppression. The innate immune system, including monocytes, macrophages, dendritic cells (DCs), neutrophils, innate lymphoid cells and innate-like T cells, performs non-specific killing of tumor cells (30). The adaptive immune system suppresses tumor progression primarily by specifically killing tumor cells using T cells, which rely on T cells that specifically recognize tumor antigens via the TCR (31). In the equilibrium phase, the host immune system, including APCs and CTLs, maintains a dynamic balance with the tumor cells. The net growth of tumor cells is limited, and the cellular immunogenicity of tumor cells is modified by the adaptive immune system of the host, which induces changes in the host immune response. After editing, tumor cells enter the escape phase and their growth becomes unrestrained (20). The mechanism may include decreased expression of TAAs and MHC I, increased secretion of immunosuppressive cytokines (such as IL-10, IL-35, TGFβ1 and prostaglandins) and upregulation of Tregs and myeloid-derived suppressor cells (MDSCs) (32).
T cells play an important role in constraining tumor growth during the entire immunoediting process, especially in the equilibrium phase. Several studies have demonstrated that CD4+ and CD8+ T cells recognize non-self-peptide epitopes (antigens) expressed on tumor cells (33–35). These antigens are often translated from somatically mutated genes or developed from oncoviral antigens (36,37). MHC I molecules present tumor antigens to TCRs on CTLs to initiate T cell proliferation and activation (27). However, whether CTLs can be activated is determined by costimulatory or coinhibitory signals. After T cells receive simultaneous binding of co-stimulatory ligands and tumor antigen/MHC complexes, they initiate a series of processes, including cytokine production, anti-apoptotic factor production and cell cycle progression, for their proliferation and differentiation (38).
The molecular mechanisms of various co-stimulatory signals have been elucidated, and the classical co-stimulatory signal being the B7-CD28 signal. The co-stimulatory receptor CD28 provides a activation signal for T-cell after binding to ligand B7 expressed on APCs (38). Other costimulatory receptors such as CD27, CD40L, CD134 and CD137 also contribute to costimulation and are mainly detected in tumor antigen-activated T cells (39–42). Binding of co-inhibitory receptors on CTLs and their ligands on tumor cells induces T cell inactivation. This inhibition is mainly mediated by two signaling pathways: Programmed death protein 1 (PD-1) and its ligand, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (43).
PD-1 has two ligands: PD-L1, which is mainly expressed on different tumor cells, and PD-L2, which is mainly expressed on APCs. After PD-1 binds to its ligand PD-L1, TCR-signaling interferes with the inhibition of the T-cell response (44,45). PD-L2 has a higher affinity for PD-1 compared with PD-L1; however, the function of PD-L2 is not fully defined. Studies have shown that the combination of PD-L2 and PD-1 promotes CD4+ T cell proliferation and cytokine secretion (46,47).
The ligands of CTLA-4 are B7-1 and B7-2, which are the same ligands as CD28. CTLA-4 has greater avidity for B7 compared with CD28, and its competitive binding prevents CD28 costimulation signaling and immunosuppression (48,49).
Other co-inhibitory receptors, including T cell immunoglobulin, mucin domain containing-3 and indoleamine 2,3-dioxygenase (IDO), also contribute to tumor immune evasion (38).
Forkhead box P3+ (FOXP3+) Tregs are immunosuppressive T cells that suppress the immune functions of effector T cells. In the tumor immune microenvironment, FOXP3+ Tregs play an important role in homeostatic regulation and escape phase of cancer immunoediting (50). Studies have shown that the underlying mechanisms may be as follows: i) Tregs can engage APC co-stimulatory receptors to weaken APC-to-naïve/effector cells signals; ii) Tregs suppress the activity of effector T cells and APCs by secreting inhibitory cytokines such as IL-35 and IL-10; iii) Tregs compete with effector cells for binding to APC signals and cytokines; iv) Tregs produce perforin/granzymes, which act on effector cells to induce apoptosis; and v) in tumors, death of Tregs converts ATP to adenosine, which affects T cell function by binding to receptors on T cells (51,52).
Characters of the T cell-related immune microenvironment in GC
In general, when tumor tissue and surrounding stroma are infiltrated with CD8+ T cells, the tumor may have an improved prognosis and response to immunotherapies (53,54). This infiltration of T cells indicates the continued presence of an immune response in the TME (55). In previous years, an increasing number of studies have demonstrated the value of tumor-infiltrating lymphocytes (TILs) as prognostic indicators (56–58). As CTLs, CD8+ T cells can kill tumor cells directly; therefore, a number of studies have focused on the relationship between tumor infiltration density and patient outcomes (31,59,60). In GC, some studies have shown that a higher density of tumor-infiltrating CD3+ or CD8+ T cells is associated with an improved prognosis (61,62). Gene set enrichment analysis has been performed to determine the transcriptional signature of the TILs immune response in the TME. Interferon γ (IFNγ) is one of the genes representing a rich presence of TILs and an improved prognosis (54).
However, CTLs, such as CD8+ T cells, are not the only types of cells in TILs. CD4+ Th cells, CD45RO+ memory T cells and FOXP3+ Tregs are also present in the T cells of TILs (63). Owing to the functions of different infiltrating T cells, TILs play a bidirectional regulatory role in the tumor and host immune response microenvironment. During the elimination phase of cancer immunoediting, tumor antigens are captured and presented for the priming and activation of CTLs. The trafficking of CTLs leads to their infiltration into tumors, where cytokines such as IFNγ are released to augment anti-tumor effects (25,64). In the equilibrium phase, CTLs continue to inhibit the growth of tumor cells that have acquired partial means of immune escape (65). However, tumor cells that enter the escape phase cannot be killed by CTLs because of a lack of immunological recognition and can recruit multiple immunosuppressive cells (66). As immunosuppressive cells, Tregs in TILs contribute to the cancer progression. The enrichment of Tregs in the TME may be caused by the metabolite pathway through which the tumor gains energy, specifically the fatty acid pathway (67).
In patients with GC, FOXP3+ Tregs appear to be associated with H. pylori infection. A previous study shows that the number of FOXP3+ Tregs is significantly higher in H. pylori-infected GC compared with in non-infected GC (68). Moreover, eradication of H. pylori decreases the infiltration level of Tregs in gastric mucosa (69). Studies have shown that the infiltration of Tregs to the gastric mucosa increases the expression levels of FOXP3, TGF-β and IL-10, resulting in the suppression of the immune response and persistence of H. pylori infection (70,71).
In GC, the two main mechanisms by which Tregs infiltrate the TME are the induction of differentiation and increased recruitment. In patients with Epstein Barr virus (EBV)-positive GC, increased recruitment of CCL22 produced by EBV and decreased emigration due to CCR7 downregulation on Tregs may promote the accumulation of Tregs in the TME (72). Additionally, studies have shown that CCL22 and CCL17 induce the migration of Tregs to the TME in GC (73). A number of studies have explored the mechanisms by which different types of T cells are induced to differentiate into Tregs. CD19+ CD24high CD38high regulatory B cells (Bregs) may induce the differentiation of CD4+ CD25− effector T cells to FOXP3+ Tregs via TGF-β1 by suppressing the secretion of IFN-γ and TNF-α by Th cells (74). GC cells can produce TGF-β and IL-10 to induce differentiation of naïve CD4+ T cells into Tregs (75–77). Moreover, IDO is associated with poor prognosis in GC by attenuating Treg activation (78). IL-35 is another hotspot in Treg-related tumor immunity research. It is secreted by Tregs and promotes Treg proliferation. IL-35 derived from Tregs induces intra-tumoral T cell exhaustion by upregulating multiple inhibitory receptors, including PD-1, TIM-3 and LAG-3 (79). In GC, the population of IL-35-producing Bregs is related to the frequency of Tregs, MDSCs and CD14 monocytes and the elevation of IL-35-producing Bregs can result in a poor prognosis of GC (80).
The balance between different types of T cells in the TME in tumor development has attracted increasing attention. Numerous studies have shown that the balance between Th17 cells and Tregs, two different subsets of CD4+T cells, is important for maintaining the tumor immune response (81). Tregs are derived from CD4+T cell differentiation induced by TGF-β and IL-2 and play a role in immunosuppression and tumor promotion (82). Th17 cells, induced by TGF-β and IL-6, are effector lymphocytes primarily involved in anti-infection and promoting autoimmunity (83). The effect of Th17 cells on tumor promotion or inhibition depends on the type of tumor (84,85), and a number of studies have shown that Th17 cells mainly play a role in tumor inhibition in GC (86–88). One study has showed that disruption of the Treg/Th17 balance by GC tissue-derived mesenchymal stem cells (GC-MSCs) can result in immunosuppression in the GC TME (87). TGF-β, IL-6 and IL-10 derived from GC-MSCs can facilitate the differentiation of Tregs (89), while the secretion of PGE2 and IFN-γ can inhibit the differentiation of Th17 cells (90,91). Observation of human GC pathological specimens has shown that the ratio of Th17 cells/Tregs in TILs is significantly higher in early cases compared with advanced cases. The number of Th17 cells decreases, whereas the number of Tregs increases with disease progression (88). In H. pylori-induced GC, an increased ratio of IL-10/IFN-γ correspondingly increases the ratio of Treg/Th17 (92). A study of T cell subsets in human GC shows that the number of CD11b+ PD-L1+ DCs, neutrophils and Tregs in metastatic tumor-draining lymph nodes are significantly higher compared with those in metastatic-free nodes, skewing CD4+ effector T cells towards immune tolerance in the TME (93). These studies show that the imbalance of different subsets of T cells may explain why Tregs infiltrate the GC TME.
Current strategies of immunotherapy for GC
Immune-checkpoint inhibitors (ICIs)
Genomic analysis of the TME in patients with GC shows a high inflammatory character and high tumor mutational burden, indicating a continued but suppressed immune response in the GC TME (94). According to the aforementioned theory, immune checkpoint molecules play an important role in tumor progression in the TME. Studies have shown that GC tissues have more infiltrated T cells with a high expression of PD-1 compared with normal tissues, and they secrete a lower level of IFN-γ (95). A study on human GC specimens confirms that PD-L1 expression reaches 42.2%, while no PD-L1 is detectable in normal gastric tissues. Patients with high PD-L1 expression have a larger tumor diameter, deeper invasion depth, more lymph node metastases and a poorer prognosis (96). Similarly, another study has shown that CTLA-4 is expressed in 86.6% of GC samples, and that CTLA-4 positivity is associated with inferior overall survival (97). Based on these findings, inhibitors of PD-1 and CTLA-4 are promising ICIs, and numerous clinical studies on these ICIs are in progress (Table I).
To inhibit the PD-1/L1 axis, inhibitors can target either PD-1 or PD-L1. Nivolumab and pembrolizumab are two major PD-1 monoclonal antibodies for GC under clinical research. Avelumab and durvalumab are the two major PD-L1 monoclonal antibodies used to treat GC under clinical research. All have been approved for the immunotherapy of other solid tumors based on the promising results of clinical trials (98–101).
Pembrolizumab has also shown promising clinical benefits in GC. A multicenter, open-label, phase 1b KEYNOTE-012 study of PD-L1-positive recurrent or metastatic GC/adenocarcinoma of esophagogastric junction (AEG) shows a 22% overall/objective response rate (ORR) to pembrolizumab and a manageable toxicity effect. The IFN-γ signature score in responders shows a higher trend compared with those in non-responders (P=0.070) in 30 evaluable samples (102). The multicenter, single-arm, phase 2 KEYNOTE-059 study further confirms the clinical benefit of pembrolizumab in patients with GC/AEG with tumor progression after receiving two or more lines of treatment. The number of enrollments is 259, with an ORR of 11.6% and a complete response rate of 2.3% (95% CI, 0.9–5.0%). The ORR is 15.5% in PD-L1 positive and 6.4% in PD-L1 negative patients. The 18-gene T-cell-inflamed gene expression profiling score for the aforementioned patients has been evaluated, and the results show that the scores for responders are higher compared with those for non-responders (103). However, in the phase 3 KEYNOTE-061 study, pembrolizumab does not show a significant overall survival (OS) benefit with second-line treatment for AGC/AEG with PD-L1 (104). A similar result has been observed for first-line treatment in the KEYNOTE-062 trial, where patients with PD-L1 positive, HER2 negative AGC/AEG treated with pembrolizumab do not have an improved OS when compared with patients treated with standard chemotherapy (105). However, in the phase 3 KEYNOTE-811 study, the addition of pembrolizumab to standard treatment with trastuzumab plus chemotherapy significantly improves the objective response rate in patients with unresectable or metastatic HER2-positive GC/AEG (ORR, pembrolizumab 74.4% vs. placebo 51.7%) (106). The multicenter, randomized, phase 3 KEYNOTE-585 study shows that pembrolizumab plus chemotherapy for resectable advanced GC/AEG has a significantly improved pathological complete response rate, but no benefits in OS (107). A phase 2 first-line study (registration no. NCT04249739) using single-cell RNA-sequencing to explore changes in immune cells after pembrolizumab plus chemotherapy for advanced gastroesophageal junctional adenocarcinoma shows that pembrolizumab increases the infiltration of CD8+T cells in the TME (108).
Nivolumab is another commonly used PD-1 monoclonal antibody for GC. The multicenter, phase 1/2 CheckMate-032 trial shows that nivolumab and nivolumab plus ipilimumab have clinically meaningful antitumor activities (100). Furthermore, an open-label, phase 3 CheckMate 649 trial has evaluated the clinical benefit of nivolumab plus chemotherapy compared with chemotherapy alone as a first-line treatment for patients with AGC/AEG. Recently, the long-term follow-up results of this trial showed that the median OS and progression-free survival (PFS) of PD-L1 combined positive score (CPS) ≥5 patients treated with first-line nivolumab + chemotherapy were improved compared with patients treated with chemotherapy alone (median OS, 14.4 vs. 11.1 months) (109). Compared with chemotherapy alone, the combination of nivolumab and ipilimumab does not result in a longer OS (110). To the best of our knowledge, this is the first trial to demonstrate that PD-1 inhibitors have survival benefits in patients with GC. The randomized, double-blind, phase 3 ATTRACTION-2 trial shows that nivolumab has a significantly longer OS in patients with unresectable or recurrent AGC/AEG compared with the placebo (OS, 5.26 vs. 4.14 months) (99). In a randomized, multicenter, phase 2/3 ATTRACTION-4 trial, nivolumab plus chemotherapy has a significantly improved PFS benefit for patients with unresectable or recurrent HER2-negative AGC/AEG compared with the placebo plus chemotherapy (median PFS, nivolumab + chemotherapy 8.34 months vs. placebo + chemotherapy 6.97 months), but no benefits in OS (111). A recent randomized, double-blind, phase 3 ORIENT-16 trial reports that the PD1 inhibitor sintilimab plus chemotherapy improves the OS of patients with unresectable GC/AEG and has a CPS score of ≥5 compared with placebo plus chemotherapy (median OS, sintilimab group 18.4 months vs. placebo group 12.9 months) (112). A clinical trial (registration no. NCT03453164) for unresectable advanced or recurrent GC shows that nivolumab plus radiotherapy for advanced and unresectable GC can promote CD4+T and CD8+T cell activation (113).
Clinical research on GC immunotherapy with avelumab and durvalumab has shown some advancements. The JAVELIN Gastric 100 study enrolled 499 patients with unresectable HER2 negative AGC/AEG who had been assessed as no disease progression after receiving induction chemotherapy with oxaliplatin and fluorouracil. Patients were randomly assigned to receive either avelumab maintenance therapy or continued chemotherapy, and long-term follow-up shows that patients receiving different treatment regimens have similar OS and PFS (114). The JAVELIN Gastric 300 study shows that single-agent avelumab for the patients with unresectable, recurrent, or metastatic GC/AEG does not bring OS and PFS benefits compared with chemotherapy (115). A phase 1b/2 study (registration no. NCT02340975) that recruited 63 GC/AEG patients with failed first-line chemotherapy shows that durvalumab plus tremelimumab does not significantly prolong OS compared with durvalumab or tremelimumab (116). A phase 2, open-label, single-center, non-randomized study (registration no. NCT03780608) included 31 patients with advanced GC who had failed chemotherapy, and the single-cell RNA-sequencing of peripheral blood showed that partial response patients treated with durvalumab plus ceralasertib have a higher tumor-reactive CD8+T cell expansion compared with patients with progressive disease (117).
Chimeric antigen receptor (CAR)-T cell therapy
CAR-T cell therapy has achieved remarkable efficacy in hematological tumors (118); however, there are still challenges in solid tumors, mainly because of the highly immunosuppressive TME. The application of CAR T-cell therapy in GC still has limitations that may be related to the heterogeneity of tumor-specific biomarkers (119). Several biomarkers that can be used for CAR-T therapy have been identified, and some have been used in the treatment of GC.
Claudin18.2 (CLDN18.2) is a molecule that is highly expressed in both the in situ and metastatic stages of GC, making it an important target for treatment. CAR-T cells targeting CLDN18.2, called CT041 (120), have been used to treat advanced GC. A multicenter, single-arm phase 1 trial (registration no. NCT03874897) for CT041 recruited 37 patients primarily with CLDN18.2-positive GC/AEG. The interim analysis indicated acceptable safety and promising efficacy for CT041 treatment (119). An ongoing single-arm, open-label, phase 1 study (NCT04404595) is also investigating the safety and efficacy of CT041 in patients with CLDN18.2-positive advanced GC/AEG (121).
HER2 is an important molecular marker of GC, and trastuzumab, which targets HER2, plays an important antitumor role in HER2-positive GC (16). HER2-specific CAR-T cell therapy has made some progress in central nervous system tumors (122), but remains in the preclinical research stage in GC. HER2-directed CAR-T cells inhibit xenograft tumor progression in GC (123). Other CAR-T cells in preclinical studies, such as cadherin 17 CAR-T cells (124), anti-prostate stem cell antigen CAR-T cells (125), CAR-T cells targeting PD-L1 (126) and mesothelin-targeting CAR-T cells (127) can exert antitumor activities in GC.
Adoptive cellular immunotherapies
Adoptive cellular immunotherapies either activate CTLs directly against tumor cells or by binding molecules expressed by tumor cells. Tumor-infiltrating or peripheral blood immune cells are isolated from the patient, expanded, activated in vitro and then reinfused into the same patient (128). Cytokine-induced killer (CIK) cells, TIL and natural killer cells are the three major cell types currently used in GC adoptive cellular immunotherapy research.
CIKs have strong cytotoxic effect on solid tumor cells and exert immunomodulatory effects via the secretion of IFN-γ and IL-2 (129). CIKs can be cultured from peripheral blood using anti-CD3 antibody, IFN-γ and IL-2 in vitro, and have cytotoxic effects on the MGC-803 GC cell line (130). Numerous clinical trials are evaluating CIK treatment combined with chemotherapy. A non-random clinical trial has shown that in patients who underwent D2 gastrectomy, CIK therapy combined with chemotherapy prolonged disease-free survival and OS compared with chemotherapy alone (131). A phase 1/2 non-randomized clinical trial is ongoing to compare the PFS of DC-CIK plus S-1 based chemotherapy with of S-1 based chemotherapy along (registration no. NCT01783951).
Adoptive cellular immunotherapies depend on the tumor-killing effect of T lymphocytes that can specifically recognize TAAs. Theoretically, the most direct way to identify these cells is to use TILs. Studies have shown that T cell populations derived from TILs can induce objective clinical responses in patients with melanoma (132–134). A randomized clinical trial has shown that using TILs as adoptive immunotherapy plus chemotherapy can prolong OS in patients with stage 4 GC compared with chemotherapy alone (135). However, in GC, TILs may stimulate tumor cell proliferation. A previous study shows that HP0175, a trans-isomerase of H. pylori, can elicit a peculiar Th17 inflammation. The inflammatory response caused by high expression of MMP-2, MMP-9 and VEGF may lead to the occurrence and progression of GC (136).
Cancer vaccines
Since the first cell-based immunotherapeutic vaccine was approved in 2010 by the Food and Drug Administration (137), a large number of studies have investigated the application value of cancer vaccines in the treatment of various tumors, including GC (138–140). The key to cancer vaccine research is the presentation of TAAs by APCs to trigger anticancer immunity (138). A phase 1/2 clinical trial has shown promising results for a vaccine against human leukocyte antigen-A24-restricted human vascular endothelial growth factor receptor 1 (VEGFR1)-1084 and VEGFR2-169 combined with chemotherapy (139). Vaccines against H. pylori can be used as tools for GC prevention and as therapeutic regimens (140).
Immunotherapy targeting Tregs
As aforementioned, Tregs play an important role in GC development. Several studies have investigated the immunosuppression mediated by Tregs, and blocking this pathway may be a potential treatment for GC (141–143). A previous study have shown that the cooperative inhibition of tumor immune response by IL-10+ and IL-35+ Tregs promotes T cell exhaustion in TME (144). The results of this study will contribute to the development of novel immunotherapy targeting Tregs, which may limit adverse events of immunotherapy. Some studies have focused on the direct depletion of Tregs. For example, a study has shown that the depletion of Tregs by oral metronomic cyclophosphamide can enhance the antitumor immune response in 9 patients with different types of metastatic solid tumors (143). Other studies have aimed to target molecules expressed on Tregs to directly block immunosuppression in the TME, such as CD25 (144–146). However, a phase 1/2 study in metastatic melanoma has shown that using an anti-CD25 monoclonal antibody to deplete CD4+ FoxP3+ CD25high Tregs does not enhance the efficacy of the DC vaccine (147).
Conclusion
Immunotherapy has achieved good results in preclinical and clinical trials for advanced GC. Immune checkpoint inhibitors are rapidly progressing and are expected to become the mainstream treatment for advanced GC within a few years, followed by cellular immunotherapy and cancer vaccine research. A combination of various immunotherapies and conventional treatment methods can reduce toxic side effects and enhance curative effects under appropriate circumstances. Matching personalized immunotherapy methods for patients with GC and ensuring safety and effectiveness may be the main development directions for immunotherapy in the future. It relies on an in-depth understanding of the mechanisms of various immunotherapies and the immune, molecular and genetic characteristics of the patient as well as clinical verification. Immunotherapy is expected to improve the treatment of GC.
Acknowledgements
Not applicable.
Funding
This work was supported by The Tianjin Key Medical Discipline (Specialty) Construction Project (grant no. TJYXZDXK-005A), The Natural Science Foundation of Tianjin Municipality (grant no. 22JCZXJC00140) and The Tianjin Science and Technology Major Special Projects (grant no. 21ZXJBSY00110).
Availability of data and materials
Not applicable.
Authors' contributions
ZZ, WZ, XL, YY and WF contributed to the study conception and design. YY and WF provided the main idea and direction for this manuscript. ZZ and WZ performed the literature search and drafted the manuscript. XL drew the table. XL, YY and WF critically revised the work. 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.
Authors' information
Mr. Zhaoxiong Zhang, ORCID 0000-0001-8668-0884; Professor Yongjia Yan, ORCID 0000-0002-9496-2766; Professor Weihua Fu, ORCID 0000-0003-2576-865X.
References
|
Hundahl SA, Phillips JL and Menck HR: The national cancer data base report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth edition American joint committee on cancer staging, proximal disease, and the ‘different disease’ hypothesis. Cancer. 88:921–932. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 355:11–20. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM and Martenson JA: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 345:725–730. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Karimi P, Islami F, Anandasabapathy S, Freedman ND and Kamangar F: Gastric cancer: Descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 23:700–713. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Thrift AP and El-Serag HB: Burden of gastric cancer. Clin Gastroenterol Hepatol. 18:534–542. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Shrihari TG: Dual role of inflammatory mediators in cancer. Ecancermedicalscience. 11:7212017. View Article : Google Scholar : PubMed/NCBI | |
|
Kershaw MH, Westwood JA and Darcy PK: Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 13:525–541. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, et al: Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 373:23–34. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al: Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 375:1823–1833. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Chia NY and Tan P: Molecular classification of gastric cancer. Ann Oncol. 27:763–769. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Guan WL, He Y and Xu RH: Gastric cancer treatment: Recent progress and future perspectives. J Hematol Oncol. 16:572023. View Article : Google Scholar : PubMed/NCBI | |
|
Shah MA, Bang YJ, Lordick F, Alsina M, Chen M, Hack SP, Bruey JM, Smith D, McCaffery I, Shames DS, et al: Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-Negative, MET-Positive gastroesophageal adenocarcinoma: The METGastric Randomized Clinical Trial. JAMA Oncol. 3:620–627. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, Wotherspoon A, Saffery C, Middleton G, Wadsley J, et al: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol. 14:481–489. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 376:687–697. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 383:31–39. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, et al: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol. 15:1224–1235. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Y and Zhang Z: The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 17:807–821. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
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 | |
|
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 373:1803–1813. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Niccolai E, Taddei A, Prisco D and Amedei A: Gastric cancer and the epoch of immunotherapy approaches. World J Gastroenterol. 21:5778–5793. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
St Paul M and Ohashi PS: The roles of CD8+ T cell subsets in antitumor immunity. Trends Cell Biol. 30:695–704. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Ruterbusch M, Pruner KB, Shehata L and Pepper M: In Vivo CD4+ T cell differentiation and function: Revisiting the Th1/Th2 Paradigm. Annu Rev Immunol. 38:705–725. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Chen DS and Mellman I: Oncology meets immunology: The cancer-immunity cycle. Immunity. 39:1–10. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Kim JM and Chen DS: Immune escape to PD-L1/PD-1 blockade: Seven steps to success (or failure). Ann Oncol. 27:1492–1504. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Jhunjhunwala S, Hammer C and Delamarre L: Antigen presentation in cancer: Insights into tumour immunogenicity and immune evasion. Nat Rev Cancer. 21:298–312. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF and Sancho D: Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 20:7–24. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Ozga AJ, Chow MT and Luster AD: Chemokines and the immune response to cancer. Immunity. 54:859–874. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Yi M, Li T, Niu M, Mei Q, Zhao B, Chu Q, Dai Z and Wu K: Exploiting innate immunity for cancer immunotherapy. Mol Cancer. 22:1872023. View Article : Google Scholar : PubMed/NCBI | |
|
Gajewski TF, Schreiber H and Fu YX: Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 14:1014–1022. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Finn OJ: A Believer's overview of cancer immunosurveillance and immunotherapy. J Immunol. 200:385–391. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Poschke I, Faryna M, Bergmann F, Flossdorf M, Lauenstein C, Hermes J, Hinz U, Hank T, Ehrenberg R, Volkmar M, et al: Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma. Oncoimmunology. 5:e12408592016. View Article : Google Scholar : PubMed/NCBI | |
|
Balachandran VP, Luksza M, Zhao JN, Makarov V, Moral JA, Remark R, Herbst B, Askan G, Bhanot U, Senbabaoglu Y, et al: Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 551:512–516. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Schumacher TN and Schreiber RD: Neoantigens in cancer immunotherapy. Science. 348:69–74. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Coulie PG, Van den Eynde BJ, van der Bruggen P and Boon T: Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer. 14:135–146. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Lee CH, Yelensky R, Jooss K and Chan TA: Update on tumor neoantigens and their utility: Why It is good to be different. Trends Immunol. 39:536–548. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Chen L and Flies DB: Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 13:227–242. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Flieswasser T, Van den Eynde A, Van Audenaerde J, De Waele J, Lardon F, Riether C, de Haard H, Smits E, Pauwels P and Jacobs J: The CD70-CD27 axis in oncology: the new kids on the block. J Exp Clin Cancer Res. 41:122022. View Article : Google Scholar : PubMed/NCBI | |
|
Tang T, Cheng X, Truong B, Sun L, Yang X and Wang H: Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacol Ther. 219:1077092021. View Article : Google Scholar : PubMed/NCBI | |
|
Schwartz RH: T cell anergy. Annu Rev Immunol. 21:305–334. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P and Hodes RJ: Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science. 262:905–907. 1993. View Article : Google Scholar : PubMed/NCBI | |
|
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 515:568–571. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Maeda TK, Sugiura D, Okazaki IM, Maruhashi T and Okazaki T: Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J Biol Chem. 294:6017–6026. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Patsoukis N, Wang Q, Strauss L and Boussiotis VA: Revisiting the PD-1 pathway. Sci Adv. 6:eabd27122020. View Article : Google Scholar : PubMed/NCBI | |
|
Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, et al: PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2:261–268. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB and Bluestone JA: CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1:405–413. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Krummel MF and Allison JP: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 182:459–465. 1995. View Article : Google Scholar : PubMed/NCBI | |
|
Moreno Ayala MA, Campbell TF, Zhang C, Dahan N, Bockman A, Prakash V, Feng L, Sher T and DuPage M: CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity. Immunity. 56:1613–1630.e5. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Caridade M, Graca L and Ribeiro RM: Mechanisms Underlying CD4+ Treg immune regulation in the adult: From experiments to models. Front Immunol. 4:3782013. View Article : Google Scholar : PubMed/NCBI | |
|
Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S, Zhao L, Vatan L, Shao I, Szeliga W, et al: Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol. 18:1332–1341. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Chen DS and Mellman I: Elements of cancer immunity and the cancer-immune set point. Nature. 541:321–330. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, et al: IFN-ү-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 127:2930–2940. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Gajewski TF: The next hurdle in cancer immunotherapy: Overcoming the Non-T-Cell-inflamed tumor microenvironment. Semin Oncol. 42:663–671. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Kang BW, Seo AN, Yoon S, Bae HI, Jeon SW, Kwon OK, Chung HY, Yu W, Kang H and Kim JG: Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer. Ann Oncol. 27:494–501. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Kim Y, Rhee YY, Wen X, Cho NY, Bae JM, Kim WH and Kang GH: Combination of L1 methylation and tumor-infiltrating lymphocytes as prognostic marker in advanced gastric cancer. Gastric Cancer. 23:464–472. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Pötzsch M, Berg E, Hummel M, Stein U, von Winterfeld M, Jöhrens K, Rau B, Daum S and Treese C: Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression. Oncoimmunology. 9:18246322020. View Article : Google Scholar : PubMed/NCBI | |
|
Huang H, Huang Z, Ge J, Yang J, Chen J, Xu B, Wu S, Zheng X, Chen L, Zhang X and Jiang J: CD226 identifies functional CD8+T cells in the tumor microenvironment and predicts a better outcome for human gastric cancer. Front Immunol. 14:11508032023. View Article : Google Scholar : PubMed/NCBI | |
|
Wang J, Li R, Cao Y, Gu Y, Fang H, Fei Y, Lv K, He X, Lin C, Liu H, et al: Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer. Nat Commun. 12:30802021. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang W, Liu K, Guo Q, Cheng J, Shen L, Cao Y, Wu J, Shi J, Cao H, Liu B, et al: Tumor-infiltrating immune cells and prognosis in gastric cancer: A systematic review and meta-analysis. Oncotarget. 8:62312–62329. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Zheng X, Song X, Shao Y, Xu B, Chen L, Zhou Q, Hu W, Zhang D, Wu C, Tao M, et al: Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: A meta-analysis. Oncotarget. 8:57386–57398. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Corthay A, Skovseth DK, Lundin KU, Røsjø E, Omholt H, Hofgaard PO, Haraldsen G and Bogen B: Primary antitumor immune response mediated by CD4+ T cells. Immunity. 22:371–383. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Kang BW, Kim JG, Lee IH, Bae HI and Seo AN: Clinical significance of tumor-infiltrating lymphocytes for gastric cancer in the era of immunology. World J Gastrointest Oncol. 9:293–299. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Vesely MD, Kershaw MH, Schreiber RD and Smyth MJ: Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 29:235–271. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Willimsky G and Blankenstein T: Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature. 437:141–146. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Kim JK, Klinger M, Benjamin J, Xiao Y, Erle DJ, Littman DR and Killeen N: Impact of the TCR signal on regulatory T cell homeostasis, function, and trafficking. PLoS One. 4:e65802009. View Article : Google Scholar : PubMed/NCBI | |
|
From the American Association of Neurological Surgeons (AANS), American Society of Neuroradiology (ASNR), Cardiovascular and Interventional Radiology Society of Europe (CIRSE), Canadian Interventional Radiology Association (CIRA), Congress of Neurological Surgeons (CNS), European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), European Stroke Organization (ESO), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Interventional Radiology (SIR) et al., . Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int J Stroke. 13:612–632. 2018.PubMed/NCBI | |
|
Chen T, Jin R, Huang Z, Hong W, Chen Z and Wang J: The variation of expression of CD4+ CD25+ Foxp3+ regulatory T cells in patients with Helicobacter pylori infection and eradication. Hepatogastroenterology. 61:507–511. 2014.PubMed/NCBI | |
|
Wu YY, Chen JH, Kao JT, Liu KC, Lai CH, Wang YM, Hsieh CT, Tzen JT and Hsu PN: Expression of CD25(high) regulatory T cells and PD-1 in gastric infiltrating CD4(+) T lymphocytes in patients with Helicobacter pylori infection. Clin Vaccine Immunol. 18:1198–1201. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Lundgren A, Stromberg E, Sjoling A, Lindholm C, Enarsson K, Edebo A, Johnsson E, Suri-Payer E, Larsson P, Rudin A, et al: Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients. Infect Immun. 73:523–531. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang NN, Chen JN, Xiao L, Tang F, Zhang ZG, Zhang YW, Feng ZY, Jiang Y and Shao CK: Accumulation Mechanisms of CD4(+)CD25(+)FOXP3(+) Regulatory T Cells in EBV-associated gastric carcinoma. Sci Rep. 5:180572015. View Article : Google Scholar : PubMed/NCBI | |
|
Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H and Fujii H: CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer. 122:2286–2293. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Wang WW, Yuan XL, Chen H, Xie GH, Ma YH, Zheng YX, Zhou YL and Shen LS: CD19+CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget. 6:33486–33499. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Hu JL, Yang Z, Tang JR, Fu XQ and Yao LJ: Effects of gastric cancer cells on the differentiation of Treg cells. Asian Pac J Cancer Prev. 14:4607–4610. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Lu X, Liu J, Li H, Li W, Wang X, Ma J, Tong Q, Wu K and Wang G: Conversion of intratumoral regulatory T cells by human gastric cancer cells is dependent on transforming growth factor-β1. J Surg Oncol. 104:571–577. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Yuan XL, Chen L, Zhang TT, Ma YH, Zhou YL, Zhao Y, Wang WW, Dong P, Yu L, Zhang YY and Shen LS: Gastric cancer cells induce human CD4+Foxp3+ regulatory T cells through the production of TGF-β1. World J Gastroenterol. 17:2019–2027. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Nishi M, Yoshikawa K, Higashijima J, Tokunaga T, Kashihara H, Takasu C, Ishikawa D, Wada Y and Shimada M: The Impact of Indoleamine 2,3-dioxygenase (IDO) expression on stage III gastric cancer. Anticancer Res. 38:3387–3392. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Turnis ME, Sawant DV, Szymczak-Workman AL, Andrews LP, Delgoffe GM, Yano H, Beres AJ, Vogel P, Workman CJ and Vignali DA: Interleukin-35 limits anti-tumor immunity. Immunity. 44:316–329. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Wang K, Liu J and Li J: IL-35-producing B cells in gastric cancer patients. Medicine (Baltimore). 97:e07102018. View Article : Google Scholar : PubMed/NCBI | |
|
Knochelmann HM, Dwyer CJ, Bailey SR, Amaya SM, Elston DM, Mazza-McCrann JM and Paulos CM: When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol. 15:458–469. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL and Kuchroo VK: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 441:235–238. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM and Stockinger B: TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 24:179–189. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pagès F and Galon J: Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 71:1263–1271. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Horlock C, Stott B, Dyson PJ, Morishita M, Coombes RC, Savage P and Stebbing J: The effects of trastuzumab on the CD4+CD25+FoxP3+ and CD4+IL17A+ T-cell axis in patients with breast cancer. Br J Cancer. 100:1061–1067. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Wang B, Zhang Z, Liu W and Tan B: Targeting regulatory T cells in gastric cancer: Pathogenesis, immunotherapy, and prognosis. Biomed Pharmacother. 158:1141802023. View Article : Google Scholar : PubMed/NCBI | |
|
Wang M, Chen B, Sun XX, Zhao XD, Zhao YY, Sun L, Xu CG, Shen B, Su ZL, Xu WR and Zhu W: Gastric cancer tissue-derived mesenchymal stem cells impact peripheral blood mononuclear cells via disruption of Treg/Th17 balance to promote gastric cancer progression. Exp Cell Res. 361:19–29. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Maruyama T, Kono K, Mizukami Y, Kawaguchi Y, Mimura K, Watanabe M, Izawa S and Fujii H: Distribution of Th17 cells and FoxP3(+) regulatory T cells in tumor-infiltrating lymphocytes, tumor-draining lymph nodes and peripheral blood lymphocytes in patients with gastric cancer. Cancer Sci. 101:1947–1954. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Cao W, Cao K, Cao J, Wang Y and Shi Y: Mesenchymal stem cells and adaptive immune responses. Immunol Lett. 168:147–153. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Ghannam S, Pene J, Moquet-Torcy G, Jorgensen C and Yssel H: Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol. 185:302–312. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Liu X, Ren S, Qu X, Ge C, Cheng K and Zhao RC: Mesenchymal stem cells inhibit Th17 cells differentiation via IFN-ү-mediated SOCS3 activation. Immunol Res. 61:219–229. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Lin R, Ma H, Ding Z, Shi W, Qian W, Song J and Hou X: Bone marrow-derived mesenchymal stem cells favor the immunosuppressive T cells skewing in a Helicobacter pylori model of gastric cancer. Stem Cells Dev. 22:2836–2848. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Okita Y, Ohira M, Tanaka H, Tokumoto M, Go Y, Sakurai K, Toyokawa T, Kubo N, Muguruma K, Sawada T, et al: Alteration of CD4 T cell subsets in metastatic lymph nodes of human gastric cancer. Oncol Rep. 34:639–647. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Chen YP, Zhang Y, Lv JW, Li YQ, Wang YQ, He QM, Yang XJ, Sun Y, Mao YP, Yun JP, et al: Genomic analysis of tumor microenvironment immune types across 14 solid cancer types: Immunotherapeutic implications. Theranostics. 7:3585–3594. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Saito H, Kuroda H, Matsunaga T, Osaki T and Ikeguchi M: Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer. J Surg Oncol. 107:517–522. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG and Xu N: Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 108:19–24. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Schlosser HA, Drebber U, Kloth M, Thelen M, Rothschild SI, Haase S, Garcia-Marquez M, Wennhold K, Berlth F, Urbanski A, et al: Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma. Oncoimmunology. 5:e11007892015. View Article : Google Scholar : PubMed/NCBI | |
|
Marcus L, Lemery SJ, Keegan P and Pazdur R: FDA approval summary: Pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 25:3753–3758. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, et al: Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 390:2461–2471. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, et al: CheckMate-032 Study: Efficacy and Safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol. 36:2836–2844. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, et al: Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 383:1218–1230. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, Eder JP, Golan T, Le DT, Burtness B, et al: Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): A multicentre, open-label, phase 1b trial. Lancet Oncol. 17:717–726. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, et al: Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 4:e1800132018. View Article : Google Scholar : PubMed/NCBI | |
|
Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, et al: Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): A randomised, open-label, controlled, phase 3 trial. Lancet. 392:123–133. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, et al: Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 Phase 3 Randomized clinical trial. JAMA Oncol. 6:1571–1580. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Janjigian YY, Kawazoe A, Yañez P, Li N, Lonardi S, Kolesnik O, Barajas O, Bai Y, Shen L, Tang Y, et al: The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 600:727–730. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Shitara K, Rha SY, Wyrwicz LS, Oshima T, Karaseva N, Osipov M, Yasui H, Yabusaki H, Afanasyev S, Park YK, et al: Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): An interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol. 25:212–224. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
An M, Mehta A, Min BH, Heo YJ, Wright SJ, Parikh M, Bi L, Lee H, Kim TJ, Lee SY, et al: Early immune remodeling steers clinical response to first-line chemoimmunotherapy in advanced gastric cancer. Cancer Discov. 14:766–785. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, et al: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet. 398:27–40. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, et al: Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 603:942–948. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, et al: Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): A randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 23:234–247. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Xu J, Jiang H, Pan Y, Gu K, Cang S, Han L, Shu Y, Li J, Zhao J, Pan H, et al: Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: The ORIENT-16 Randomized clinical trial. JAMA. 330:2064–2074. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Mimura K, Ogata T, Nguyen PHD, Roy S, Kared H, Yuan YC, Fehlings M, Yoshimoto Y, Yoshida D, Nakajima S, et al: Combination of oligo-fractionated irradiation with nivolumab can induce immune modulation in gastric cancer. J Immunother Cancer. 12:e0083852024. View Article : Google Scholar : PubMed/NCBI | |
|
Moehler M, Dvorkin M, Boku N, Özgüroğlu M, Ryu MH, Muntean AS, Lonardi S, Nechaeva M, Bragagnoli AC, Coşkun HS, et al: Phase III trial of avelumab maintenance after first-line induction chemotherapy versus continuation of chemotherapy in patients with gastric cancers: Results From JAVELIN Gastric 100. J Clin Oncol. 39:966–977. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Bang YJ, Ruiz EY, Van Cutsem E, Lee KW, Wyrwicz L, Schenker M, Alsina M, Ryu MH, Chung HC, Evesque L, et al: Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 29:2052–2060. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Kelly RJ, Lee J, Bang YJ, Almhanna K, Blum-Murphy M, Catenacci DVT, Chung HC, Wainberg ZA, Gibson MK, Lee KW, et al: Safety and efficacy of durvalumab and tremelimumab alone or in combination in patients with advanced gastric and gastroesophageal junction adenocarcinoma. Clin Cancer Res. 26:846–854. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Kwon M, Kim G, Kim R, Kim KT, Kim ST, Smith S, Mortimer PGS, Hong JY, Loembé AB, Irurzun-Arana I, et al: Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer. J Immunother Cancer. 10:e0050412022. View Article : Google Scholar : PubMed/NCBI | |
|
Ali S, Kjeken R, Niederlaender C, Markey G, Saunders TS, Opsata M, Moltu K, Bremnes B, Grønevik E, Muusse M, et al: The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the treatment of acute lymphoblastic leukemia and diffuse Large B-Cell Lymphoma. Oncologist. 25:e321–e327. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Qi C, Gong J, Li J, Liu D, Qin Y, Ge S, Zhang M, Peng Z, Zhou J, Cao Y, et al: Claudin18.2-specific CAR T cells in gastrointestinal cancers: Phase 1 trial interim results. Nat Med. 28:1189–1198. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang H, Shi Z, Wang P, Wang C, Yang L, Du G, Zhang H, Shi B, Jia J, Li Q, et al: Claudin18.2-Specific chimeric antigen receptor engineered T cells for the treatment of gastric cancer. J Natl Cancer Inst. 111:409–418. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Botta GP, Chao J, Ma H, Hahn M, Sierra G, Jia J, Hendrix AY, Nolte Fong JV, Ween A, Vu P, et al: Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells. J Immunother Cancer. 12:e0079272024. View Article : Google Scholar : PubMed/NCBI | |
|
Vitanza NA, Johnson AJ, Wilson AL, Brown C, Yokoyama JK, Künkele A, Chang CA, Rawlings-Rhea S, Huang W, Seidel K, et al: Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: An interim analysis. Nat Med. 27:1544–1552. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Song Y, Tong C, Wang Y, Gao Y, Dai H, Guo Y, Zhao X, Wang Y, Wang Z, Han W and Chen L: Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo. Protein Cell. 9:867–878. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Feng Z, He X, Zhang X, Wu Y, Xing B, Knowles A, Shan Q, Miller S, Hojnacki T, Ma J, et al: Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues. Nat Cancer. 3:581–594. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Wu D, Lv J, Zhao R, Wu Z, Zheng D, Shi J, Lin S, Wang S, Wu Q, Long Y, et al: PSCA is a target of chimeric antigen receptor T cells in gastric cancer. Biomark Res. 8:32020. View Article : Google Scholar : PubMed/NCBI | |
|
Qin L, Zhao R, Chen D, Wei X, Wu Q, Long Y, Jiang Z, Li Y, Wu H, Zhang X, et al: Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth. Biomark Res. 8:192020. View Article : Google Scholar : PubMed/NCBI | |
|
Lv J, Zhao R, Wu D, Zheng D, Wu Z, Shi J, Wei X, Wu Q, Long Y, Lin S, et al: Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer. J Hematol Oncol. 12:182019. View Article : Google Scholar : PubMed/NCBI | |
|
Chan JD, Lai J, Slaney CY, Kallies A, Beavis PA and Darcy PK: Cellular networks controlling T cell persistence in adoptive cell therapy. Nat Rev Immunol. 21:769–784. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Li GX, Zhao SS, Zhang XG, Wang WH, Liu J, Xue KW, Li XY, Guo YX and Wang LH: Comparison of the proliferation, cytotoxic activity and cytokine secretion function of cascade primed immune cells and cytokine-induced killer cells in vitro. Mol Med Rep. 12:2629–2635. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Sun S, Li XM, Li XD and Yang WS: Studies on inducing apoptosis effects and mechanism of CIK cells for MGC-803 gastric cancer cell lines. Cancer Biother Radiopharm. 20:173–180. 2005.PubMed/NCBI | |
|
Chen Y, Guo ZQ, Shi CM, Zhou ZF, Ye YB and Chen Q: Efficacy of adjuvant chemotherapy combined with immunotherapy with cytokine-induced killer cells for gastric cancer after d2 gastrectomy. Int J Clin Exp Med. 8:7728–7736. 2015.PubMed/NCBI | |
|
Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH and White DE: Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 86:1159–1166. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
van den Berg JH, Heemskerk B, van Rooij N, Gomez-Eerland R, Michels S, van Zon M, de Boer R, Bakker NAM, Jorritsma-Smit A, van Buuren MM, et al: Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: Boosting of neoantigen-specific T cell reactivity and long-term follow-up. J Immunother Cancer. 8:e0008482020. View Article : Google Scholar : PubMed/NCBI | |
|
Barras D, Ghisoni E, Chiffelle J, Orcurto A, Dagher J, Fahr N, Benedetti F, Crespo I, Grimm AJ, Morotti M, et al: Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma. Sci Immunol. 9:eadg79952024. View Article : Google Scholar : PubMed/NCBI | |
|
Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T and Matsumoto Y: Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: A randomized trial. Clin Cancer Res. 8:1767–1771. 2002.PubMed/NCBI | |
|
Amedei A, Munari F, Bella CD, Niccolai E, Benagiano M, Bencini L, Cianchi F, Farsi M, Emmi G, Zanotti G, et al: Helicobacter pylori secreted peptidyl prolyl cis, trans-isomerase drives Th17 inflammation in gastric adenocarcinoma. Intern Emerg Med. 9:303–309. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 363:411–422. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Matsueda S and Graham DY: Immunotherapy in gastric cancer. World J Gastroenterol. 20:1657–1666. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Masuzawa T, Fujiwara Y, Okada K, Nakamura A, Takiguchi S, Nakajima K, Miyata H, Yamasaki M, Kurokawa Y, Osawa R, et al: Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer. Int J Oncol. 41:1297–1304. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Talebi Bezmin Abadi A: Vaccine against Helicobacter pylori: Inevitable approach. World J Gastroenterol. 22:3150–3157. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Sawant DV, Yano H, Chikina M, Zhang Q, Liao M, Liu C, Callahan DJ, Sun Z, Sun T, Tabib T, et al: Adaptive plasticity of IL-10(+) and IL-35(+) Treg cells cooperatively promotes tumor T cell exhaustion. Nat Immunol. 20:724–735. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, et al: Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 40:201–218.e9. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L and Chauffert B: Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 56:641–648. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Solomon I, Amann M, Goubier A, Arce Vargas F, Zervas D, Qing C, Henry JY, Ghorani E, Akarca AU, Marafioti T, et al: CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat Cancer. 1:1153–1166. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Sato Y, Casson CN, Matsuda A, Kim JI, Shi JQ, Iwasaki S, Chen S, Modrell B, Chan C, Tavares D, et al: Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy. Cancer Immunol Immunother. 71:2421–2431. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Campbell JR, McDonald BR, Mesko PB, Siemers NO, Singh PB, Selby M, Sproul TW, Korman AJ, Vlach LM, Houser J, et al: Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T cells in human tumor models. Cancer Res. 81:2983–2994. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Jacobs JF, Punt CJ, Lesterhuis WJ, Sutmuller RP, Brouwer HM, Scharenborg NM, Klasen IS, Hilbrands LB, Figdor CG, de Vries IJ and Adema GJ: Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: A phase I/II study in metastatic melanoma patients. Clin Cancer Res. 16:5067–5078. 2010. View Article : Google Scholar : PubMed/NCBI |
