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

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 HundeyinJuan 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

Research output: Contribution to journalArticlepeer-review

233 Scopus citations

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.

Original languageEnglish
Pages (from-to)442-454
Number of pages13
JournalNature Immunology
Volume21
Issue number4
DOIs
StatePublished - Apr 1 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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