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-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.
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Data availability
Sequence data are available in the Gene Expression Omnibus (GEO) database at NCBI under accession code GSE145905.
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Acknowledgements
We acknowledge the use of the Genome Technology, Experimental Pathology and Flow Cytometry core facilities at NYU School of Medicine. These shared resources are partially supported by the Cancer Center Support Grant, P30CA016087, at the Laura and Isaac Perlmutter Cancer Center. The Vectra3 imaging system was purchased through NIH Shared Instrument Grant S10 OD021747. This work was supported by the American College of Surgeons Resident Research Fellowship (B.D.) and NIH grants CA168611 (G.M.), CA203105 (G.M.), CA215471 (G.M.), CA19311 (G.M.) and DK106025 (G.M.).
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B.D. and S.A. prepared the manuscript, performed in vivo and in vitro experiments and data analysis, and designed, supervised and interpreted the study; M.F.C., G.S., R.D.S., D.W., C.F., K.H.T. and T.C. performed in vitro experiments; M.L, C.B, E.L., B.S., R.C., J.W. and Z.S. performed in vivo experiments in addition to manuscript and figure preparation; M.K. performed data analyis; B.A., M.S.F., S.N., J.A.K.R., E. Kruger, M.I.U.H. and J.K. performed in vivo experiments, data analysis and manuscript review; W.W., M.H. S.A.A.S, G.B., G.W., K.-K.W., J.L. and E. Kurz performed data analysis and critical review; S.S. and C.L. performed immunofluorescence; G.M. conceived, designed, supervised, analyzed and interpreted the study and provided critical review, and is senior author and corresponding author.
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G.M. has research agreements with GSK, Pfizer and Puretech Health. K.K.W. is a founder and equity holder of G1 Therapeutics and has sponsored research agreements with MedImmune, Takeda, TargImmune, Bristol-Myers Squibb, Mirati, Merus and Alkermes, and has consulting and sponsored research agreements with AstraZeneca, Janssen, Pfizer, Novartis, Merck, Ono and Array. The remaining authors declare no competing interests.
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Diskin, B., Adam, S., Cassini, M.F. et al. PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer. Nat Immunol 21, 442–454 (2020). https://doi.org/10.1038/s41590-020-0620-x
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DOI: https://doi.org/10.1038/s41590-020-0620-x
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