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

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-gamma(-) 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.