TNF-α/TNFR2 在调节性 T 细胞中对胃癌微环境和进展的影响

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.