Diskin et al. studied the relatively unexplored role of PD-L1 expression on T cells and showed that PD-L1 expression on T cells is induced by JAK-STAT signaling, tumor antigen presentation, and inflammatory cues. Conditional deletion of PD-L1 in T cells in an orthotopic KPC pancreatic tumor model enhanced intratumoral T cells and immunogenic macrophage activation. Engagement of PD-L1 by PD-1 in CD4+ T cells triggered suppressive back signaling and favored TH17 over TH1-/TH2 polarization. PD-L1+ T cells also suppressed CD4+ and CD8+ T cells in the TME and induced immunosuppressive M2-like macrophage differentiation via PD-1 ligation.
Contributed by Shishir Pant
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-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.
Author Info: (1) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (2) S. Arthur Localio Laboratory, Department of Surgery, New Yor
Author Info: (1) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (2) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (3) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (4) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (5) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (6) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (7) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (8) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (9) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (10) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (11) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (12) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (13) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (14) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (15) Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA. (16) Department of Pathology, New York University School of Medicine, New York, NY, USA. (17) Department of Pathology, New York University School of Medicine, New York, NY, USA. (18) Department of Pathology, New York University School of Medicine, New York, NY, USA. (19) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (20) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (21) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (22) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (23) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (24) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (25) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (26) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (27) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (28) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (29) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (30) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (31) Department of Pathology, New York University School of Medicine, New York, NY, USA. (32) Department of Pathology, New York University School of Medicine, New York, NY, USA. Department of Cell Biology, New York University School of Medicine, New York, NY, USA. (33) Department of Medicine, New York University School of Medicine, New York, NY, USA. (34) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. (35) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA. george.miller@nyumc.org. Department of Cell Biology, New York University School of Medicine, New York, NY, USA. george.miller@nyumc.org.
