近日,美国纽约大学医学院George Miller及其研究组的工作表明,PD-L1与T细胞的结合促进了癌症的自我耐受以及对邻近巨噬细胞和效应T细胞的抑制。 这一研究成果于2020年3月9日在线发表在《自然—免疫学》杂志上。
研究人员表示,程序性细胞死亡蛋白1(PD-1)的结合限制了T细胞的免疫原性应答。但是,在T细胞中程序性细胞死亡1配体1(PD-L1)结合的后果尚不确定。
研究人员发现,PD-L1在癌症中的T细胞表达受肿瘤抗原和无菌炎症因素的调节。PD-L1+T细胞通过三种不同的机制发挥促肿瘤耐受性:(1)PD-L1结合CD4+T细胞中的STAT3依赖性“反馈信号”,从而阻止激活,减少TH1极化和定向TH17分化。PD-L1信号还诱导CD8+T细胞为无活力的T-betIFN-γ表型,与PD-1信号传导同样具有抑制作用。(2)PD-L1+T细胞通过经典的PD-L1-PD-1信号轴抑制效应T细胞,即使在没有内源性PD-L1的情况下也足以加速肿瘤发生。(3)PD-L1+T细胞与PD-1+巨噬细胞结合,诱导了另一种M2样程序,该程序对适应性抗肿瘤免疫力产生严重影响。因此,这些研究表明,PD-L1+T细胞对肿瘤免疫具有多种耐受性。
附:英文原文
Title: PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer
Author: Brian Diskin, Salma Adam, Marcelo F. Cassini, Gustavo Sanchez, Miguel Liria, Berk Aykut, Chandan Buttar, Eric Li, Belen Sundberg, Ruben D. Salas, Ruonan Chen, Junjie Wang, Mirhee Kim, Mohammad Saad Farooq, Susanna Nguy, Carmine Fedele, Kwan Ho Tang, Ting Chen, Wei Wang, Mautin Hundeyin, Juan A. Kochen Rossi, Emma Kurz, Muhammad Israr Ul Haq, Jason Karlen, Emma Kruger, Zennur Sekendiz, Dongling Wu, Sorin A. A. Shadaloey, Gillian Baptiste, Gregor Werba, Shanmugapriya Selvaraj, Cynthia Loomis, Kwok-Kin Wong, Joshua Leinwand, George Miller
Issue&Volume: 2020-03-09
Abstract: Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent ‘back-signaling’ in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-betIFN-γ phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1–PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.
DOI: 10.1038/s41590-020-0620-x
Source: https://www.nature.com/articles/s41590-020-0620-x
Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex