The effects of TNF-α/TNFR2 in regulatory T cells on the microenvironment and progression of gastric cancer.
The effects of TNF-α/TNFR2 in regulatory T cells on the microenvironment and progression of gastric cancer.
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调节性T细胞TNF-α/TNFR2对胃癌微环境及进展的影响
DOI：
10.1002/ijc.33873
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发表时间：
2022-04-15
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
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作者：
TNFR 2+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来探讨TNFR 2 + TcR在胃癌微环境和进展中的特征和作用。肿瘤微环境中的TNFR 2 + Treg浸润水平随着胃癌进展而显著增加，并且被证明是预后标志物。单细胞RNA测序显示，肿瘤浸润性TcB中TNFR 2水平较高。TNF-α/TNFR 2信号通路被激活，伴随着共刺激分子的上调。与血液TcB不同，肿瘤浸润性TcB以激活和效应状态存在。除了表达共刺激分子如TNFR 2、4 - 1BB、0X 40和GITR之外，肿瘤浸润性TcB的特征还在于免疫检查点如CTLA-4和TIGIT以及趋化因子如CCR 6的高表达水平。体外研究表明，TNF-α/TNFR 2途径增加了CD 4 + CD 25 + T细胞中Foxp 3的表达和TGF-beta的潜在产生，并增强了TGF-beta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TNFR 2 + T细胞的高浸润水平。TNFR 2 + TGF 3浸润水平是胃癌的预后指标和独立危险因素。TNF-α/TNFR 2通路的激活促进了TcB的免疫抑制表型和功能。本研究为TNFR 2 + TcR作为胃癌治疗靶点提供了新的理论依据。 有什么新消息吗？ TNFR 2+调节性T细胞在介导免疫抑制性肿瘤微环境中发挥关键作用。然而，关于TNFR 2 + TGF 3在胃癌中的作用知之甚少。作者发现，肿瘤微环境中的TNFR 2 + Treg浸润水平随着胃癌的进展而显著增加，并作为预后标志物。体外研究表明，TNF-α/TNFR 2通路可增加CD 4 + CD 25 + T细胞中Foxp 3的水平和TGF 3中潜在的TGF-β的产生，并增强TGF 3的免疫抑制功能。总之，本研究为TNFR 2 + TGF 3作为胃癌治疗靶点提供了新的理论依据。
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. What's new? TNFR2+ regulatory T cells play a key role in mediating the immunosuppressive tumour microenvironment. However, little is known about the role of TNFR2+ Tregs in gastric cancer. The authors found that the TNFR2+ Treg infiltration level in the tumour microenvironment increased significantly as gastric cancer progressed and acted as a prognostic marker. In vitro studies showed that the TNF‐α/TNFR2 pathway can increase Foxp3 levels in CD4+CD25+ T cells and latent TGF‐β production in Tregs and enhance the immunosuppressive function of Tregs. Overall, this study provides a new theoretical basis for using TNFR2+ Tregs as a therapeutic target in gastric cancer.
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DOI：
10.1159/000289201
发表时间：
2010
期刊：
Current directions in autoimmunity
影响因子：
--
作者：
Chen X;Oppenheim JJ
通讯作者：
Oppenheim JJ
影响因子：
5.4
作者：
Chen, Xin;Subleski, Jeffrey J.;Hamano, Ryoko;Howard, O. M. Zack;Wiltrout, Robert H.;Oppenheim, Joost J.
通讯作者：
Oppenheim, Joost J.
影响因子：
168.9
作者：
Danaei, G;Vander Hoorn, S;Ezzati, M
通讯作者：
Ezzati, M
DOI：
10.4049/jimmunol.0901112
发表时间：
2009-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ruby CE;Yates MA;Hirschhorn-Cymerman D;Chlebeck P;Wolchok JD;Houghton AN;Offner H;Weinberg AD
通讯作者：
Weinberg AD
影响因子：
4.4
作者：
Elpek, Kutlu G.;Yolcu, Esma S.;Shirwan, Haval
通讯作者：
Shirwan, Haval