TNF Receptor Type II Is Critical to the Expansion and Suppressive Function of Regulatory T Cells in Malignant Pleural Effusion from Lung Cancer Patients

Abstract

Background: Tumor-infiltrating Tregs have been found to express high levels of tumor necrosis factor receptor type II (TNFR2), which renders their suppressive function more pronounced. However, the importance of TNFR2 expression on human Tregs from malignant pleural effusion (MPE) and the efficacy of targeting TNFR2 for the treatment of MPE remain unclear. Methods: The characteristics of TNFR2 expression by Tregs in MPE and peripheral blood were analyzed. The effects of TNF/TNFR2 pathway on Treg proliferation and suppressive function were explored. The relationships between effector T cells and Tregs via the TNF/TNFR2 pathway were evaluated. The effects on the percentage of CTL cells and the concentration of IFN-γ were measured after TNFR2 blockade. Findings: The percentages of Tregs in MPE were much higher than in peripheral blood. TNFR2 appears to be a specific proliferative and functional marker for Tregs in MPE. TNF promotes TNFR2+Treg proliferation and the expression of CTLA-4 and PD-L1. There is also a strong positive correlation between the level of TNF in Th17 cells and Foxp3 in CD4+CD25hi T cells, and IL-17 up-regulates the expression of TNFR2 on Tregs in vitro, suggesting Th17 cells may promote Tregs in the proliferation and function via the TNF/TNFR2 pathway. Moreover, the proportions of CTL cells and IFN-γ concentration were significantly increased after blocking TNFR2. Interpretation: Our results provide laboratorial evidence that TNFR2 might be a novel and effective target in the further clinical treatment for lung cancer patients with MPE. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (NNSFC; No. 81973990, No. 81770090 and No. 81470274) and The Graduates' Innovation Fund, Huazhong University of Science and Technology (TGI, HUST; No. 2019YGSCXCY 067). Declaration of Interests: The authors declare no potential conflicts of interests. Ethics Approval Statement: The study protocol was approved by our institutional review board for human studies, and informed consent was obtained from all subjects.