The effects of TNF‐α/TNFR2 in regulatory T cells on the microenvironment and progression of gastric cancer

Abstract

TNFR2 + regulatory T cells preferentially accumulate in the tumor microenvironment, express high levels of immunosuppressive molecules and possess strong suppressive activity. Our study aimed to explore the characteristics and role of TNFR2 + Tregs in the microenvironment and progression of gastric cancer via polychromatic immunofluorescence, single-cell RNA sequencing and flow cytometry assays. The TNFR2 + Treg infiltration level in the tumor microenvironment increased significantly as gastric cancer progressed and was demonstrated to be a prognostic marker. Single-cell RNA sequencing revealed high levels of TNFR2 in tumor-infiltrating Tregs. The TNF-α/TNFR2 signaling pathway was activated, accompanied by the upregulation of costimulatory molecules. Unlike blood Tregs, tumor-infiltrating Tregs existed in activated and effector states. In addition to expressing costimulatory molecules such as TNFR2, 4-1BB, OX40 and GITR, tumor-infiltrating Tregs were also characterized by high expression levels of immune checkpoints such as CTLA-4 and TIGIT and chemokines such as CCR6. In vitro studies showed that the TNF-α/TNFR2 pathway increased the Foxp3 expression in CD4 + CD25 + T cells and the latent TGF-β production in Tregs as well as enhanced the immunosuppressive function of Tregs. In summary, our study revealed high infiltration levels of TNFR2 + Tregs that were in activated and effector states in the tumor microenvironment. The infiltration level of TNFR2 + Tregs is a prognostic marker and an independent risk factor for gastric cancer. Activation of the TNF-α/TNFR2 pathway promotes the immunosuppressive phenotype and function of Tregs. Our study provides a new theoretical basis for TNFR2 + Tregs as a therapeutic target in gastric cancer.

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

“…have also confirmed that TNFR2 + Tregs (Figure 1 ) preferentially accumulate in TME of GC, which express high levels of CTLA‐4 and CCR6 and possess strong suppressive activity by activating the TNF‐α/TNFR2 signaling pathway. 199 In addition, the higher level of TNFR2 + Treg infiltration was correlated to a poorer prognosis in GC patients. Based on the results, targeting TNFR2 + Tregs may be an immunotherapeutic strategy for GC.…”

Tumor Necrosis Factor α: Taking a Personalized Road in Cancer Therapy

“…For instance, activation of TNFR1 by TNFα can lead to tumor cell death but under a different set of conditions it can contribute to cancer inflammation and enhance tumor progression. A similar enigma was observed for TNFR2+ tumor-infiltrating lymphocytes (TILs): TNFR2-mediated signals support the survival/activation of CD4+ T regulatory cells (Tregs) and aggravate disease course ( 46 , 60 – 67 ); however, in triple-negative breast cancer (TNBC) patients, TNFR2+ TILs were associated with improved patient survival. In parallel, mouse studies have connected reduced TNBC growth after chemotherapy with elevated presence of CD8+ TNFR2+ TILs, presumably cytotoxic T cells (CTLs) ( 68 , 69 ), agreeing with TNFR2 being required for cytotoxic activities of CD8+ T cells ( 66 ).…”

“…Then, the roles of each family member should be precisely identified in each cancer type/subtype, prior to treating patients with modulators of the pathway. This can be well-exemplified by taking the TNFR2+ TIL population as a test case: the fact that unlike published reports on the Treg identify of CD4+ TNFR2+ lymphocytes ( 46 , 60 – 67 ), TNFR2+ TILs were connected to improved survival in TNBC patients and with potential cytotoxic activities of CD8+ TNFR2+ TILs in mouse TNBC tumors ( 68 , 69 ), suggests that targeting TNFR2 in chemotherapy-treated TNBC patients may be harmful; administration of TNFα inhibitors may reduce the proliferation of CD8+ TNFR2+ CTLs and limit the potential of raising potent immune activities against the cancer cells. The detrimental consequence that may be driven by such treatments may explain the findings obtained in TNFα-/- mice that could not mount T cell-mediated anti-tumor effects ( 87 ).…”

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

“…Along with all these findings, Jiang et al (2022) and Kumar et al (2022) confirmed that with tumor progression the tissue microenvironment changes from predominance of proinflammatory effectors to predominance of immunosuppressive Tregs (34,35). Qu et al (2022) identified a distinct Treg phenotype that is increased in tumor tissue compared to patientmatched blood and defined by enriched expression of the TNF receptor superfamily member 1B (TNFR2) (30). TNFR2 + Tregs were found to be functionally immunosuppressive and an increased infiltration into tumor tissue correlated with poor prognosis.…”

“…Among the published scRNAseq gastric cancer works, it is apparent that they have undertaken various approaches to their studies. Most groups obtained primary gastric cancer tissues from patients to generate scRNAseq data (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Some utilized previously published primary tumor datasets for further analysis (36)(37)(38)(39)(40)(41)(42)(43).…”