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.

• Authors: Yang Qu, Xianhao Wang, Shuai Bai, Liling Niu, Gang Zhao, Yuan Yao, Bin Li, Hui Li
• Journal: International journal of cancer (Int J Cancer) Vol. 150 Issue 8 Pg. 1373-1391 (04 15 2022) ISSN: 1097-0215 [Electronic] United States
• PMID: 34766338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Chemical References

• Receptors, Tumor Necrosis Factor, Type II
• TNFRSF1B protein, human
• Tumor Necrosis Factor-alpha

Topics

• Adenocarcinoma (immunology, pathology)
• Adult
• Aged
• Disease Progression
• Female
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Male
• Middle Aged
• Receptors, Tumor Necrosis Factor, Type II (immunology, metabolism)
• Stomach Neoplasms (immunology, pathology)
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Tumor Microenvironment (immunology)
• Tumor Necrosis Factor-alpha (immunology, metabolism)