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

Nat Immunol. 2020 Apr;21(4):442-454. doi: 10.1038/s41590-020-0620-x. Epub 2020 Mar 9.


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-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Female
  • Humans
  • Immune Tolerance / immunology*
  • Interferon-gamma / immunology
  • Macrophages / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / immunology
  • Self Tolerance / immunology*
  • Signal Transduction / immunology
  • Tumor Microenvironment / immunology


  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma