调节性T细胞中TNF-α/TNFR2对胃癌微环境及进展的影响,International Journal of Cancer

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调节性T细胞中TNF-α/TNFR2对胃癌微环境及进展的影响
International Journal of Cancer ( IF 5.7 ) Pub Date : 2021-11-11 , DOI: 10.1002/ijc.33873
Yang Qu _{1,

2,

3} , Xianhao Wang _{1,

2,

3} , Shuai Bai _{1,

2,

3} , Liling Niu _{1,

2,

3} , Gang Zhao _{1,

2,

3} , Yuan Yao _{1,

2,

3} , Bin Li _{3,

4} , Hui Li _{1,

2,

3}

Affiliation

TNFR2 ⁺调节性T细胞优先在肿瘤微环境中积累，表达高水平的免疫抑制分子并具有很强的抑制活性。我们的研究旨在通过多色免疫荧光、单细胞 RNA 测序和流式细胞术检测探讨 TNFR2 ⁺ Tregs 在胃癌微环境和进展中的特征和作用。TNFR2 ⁺随着胃癌的进展，肿瘤微环境中的 Treg 浸润水平显着增加，并被证明是预后标志物。单细胞 RNA 测序显示肿瘤浸润性 Treg 中有高水平的 TNFR2。TNF-α/TNFR2信号通路被激活，伴随着共刺激分子的上调。与血液 Treg 不同，肿瘤浸润性 Treg 存在于激活状态和效应状态。除了表达 TNFR2、4-1BB、OX40 和 GITR 等共刺激分子外，肿瘤浸润性 Treg 还具有高表达水平的免疫检查点（如 CTLA-4 和 TIGIT）和趋化因子（如 CCR6）的特征。体外研究表明，TNF-α/TNFR2 通路增加了 CD4 ⁺ CD25 ^{+中 Foxp3 的表达。}T细胞和Tregs中潜在的TGF-β产生以及增强Tregs的免疫抑制功能。总之，我们的研究揭示了在肿瘤微环境中处于激活和效应状态的 TNFR2 ^{+ Tregs 的高浸润水平。}^{TNFR2 +} Tregs的浸润水平是胃癌的预后标志物和独立危险因素。TNF-α/TNFR2 通路的激活促进了 Tregs 的免疫抑制表型和功能。^{我们的研究为TNFR2 +} Tregs作为胃癌治疗靶点提供了新的理论依据。

"点击查看英文标题和摘要"

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

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.

更新日期：2021-11-11

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