PD-L1與T細胞的結合促進腫瘤自我耐受和免疫抑制
作者：
小柯機器人發布時間：2020/3/22 19:44:25
近日，美國紐約大學醫學院George Miller及其研究組的工作表明，PD-L1與T細胞的結合促進了癌症的自我耐受以及對鄰近巨噬細胞和效應T細胞的抑制。 這一研究成果於2020年3月9日在線發表在《自然—免疫學》雜誌上。
研究人員表示，程序性細胞死亡蛋白1（PD-1）的結合限制了T細胞的免疫原性應答。但是，在T細胞中程序性細胞死亡1配體1（PD-L1）結合的後果尚不確定。
研究人員發現，PD-L1在癌症中的T細胞表達受腫瘤抗原和無菌炎症因素的調節。PD-L1+T細胞通過三種不同的機制發揮促腫瘤耐受性：（1）PD-L1結合CD4+T細胞中的STAT3依賴性「反饋信號」，從而阻止激活，減少TH1極化和定向TH17分化。PD-L1信號還誘導CD8+T細胞為無活力的T-betIFN-γ表型，與PD-1信號傳導同樣具有抑制作用。（2）PD-L1+T細胞通過經典的PD-L1-PD-1信號軸抑制效應T細胞，即使在沒有內源性PD-L1的情況下也足以加速腫瘤發生。（3）PD-L1+T細胞與PD-1+巨噬細胞結合，誘導了另一種M2樣程序，該程序對適應性抗腫瘤免疫力產生嚴重影響。因此，這些研究表明，PD-L1+T細胞對腫瘤免疫具有多種耐受性。
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