Journal Article

PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer

Chen, Ruonan, Wang, Wei, Kruger, Emma, Leinwand, Joshua, Hundeyin, Mautin, Wu, Dongling, Loomis, Cynthia, Cassini, Marcelo F., Liria, Miguel, Buttar, Chandan, Aykut, Berk, Kim, Mirhee, Nguy, Susanna, Karlen, Jason, Wang, Junjie, Werba, Gregor, Diskin, Brian, Kurz, Emma, Tang, Kwan Ho, Selvaraj, Shanmugapriya, Salas, Ruben D., Wong, Kwok-Kin, Miller, George, Sundberg, Belen, Baptiste, Gillian, Rossi, Juan A. Kochen, Haq, Muhammad Israr Ul, Adam, Salma, Sekendiz, Zennur, Shadaloey, Sorin A. A., Li, Eric, Fedele, Carmine, Chen, Ting, Sanchez, Gustavo, Farooq, Mohammad Saad

2020

Overview

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 T H 1-polarization and directed T H 17-differentiation. PD-L1 signaling also induced an anergic T-bet − IFN-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. PD-L1 on tumor cells exerts an important dampening effect on T cells via their expression of PD-1. Miller and colleagues find that PD-L1 ‘back-signaling’ into T cells and macrophages can also dampen immune responses within the tumor microenvironment.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/580/1884/2323 / 631/67/1059/2325 / 631/67/580/1884/2323 / 631/80 / Anergy / Animals / Antitumor activity / Apoptosis / B7-H1 Antigen - immunology / Biomedical and Life Sciences / Biomedicine / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell activation / Cell death / Cell Differentiation - immunology / Cell Line, Tumor / Effector cells / Female / Health aspects / Helper cells / Humans / Immune Tolerance - immunology / Immunogenicity / Immunological tolerance / Immunology / Immunosuppression / Infectious Diseases / Inflammation / Interferon-gamma - immunology / Lymphocytes / Lymphocytes T / Macrophages / Macrophages - immunology / Male / Mice / Mice, Inbred C57BL / Patient outcomes / PD-1 protein / PD-L1 protein / Phenotypes / Programmed Cell Death 1 Receptor - immunology / Self Tolerance - immunology / Signal Transduction - immunology / Stat3 protein / T cells / Tumor cells / Tumor microenvironment / Tumor Microenvironment - immunology / Tumorigenesis / Tumors / γ-Interferon