TGF-BETA1/SMAD3 SUPPRESS ANTI-TUMOR IMMUNITY BY ENHANCING PD-1 EXPRESSION ON ANTIGEN-SPECIFIC CD8+ T CELLS IN CANCER
Park, Benjamin Vincent
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Programmed Death-1 (PD-1) is a co-inhibitory receptor that is highly expressed on exhausted tumor-infiltrating lymphocytes (TILs) in cancers and on virus-specific T cells in chronic HBV, HIV and HCV infection. Signaling through PD-1 inhibits T cell effecter function and limits effective anti-tumor and anti–viral immune responses. Despite its importance in both cancers and infectious diseases, the molecular mechanisms driving high PD-1 expression are not fully understood. In this study, we found that transforming growth factor-b1 (TGF-b1) enhances antigen-induced PD-1 expression on activated human and murine T cells in vitro and in vivo. A transcription factor, Smad, transduces signals from TGF-b superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. Inhibition of Smad3 phosphorylation or genetic deletion of Smad3 abrogates PD-1 enhancement on human and murine T cells, demonstrating that Smad3 is a critical mediator of TGF-b-effects on PD-1 regulation. In addition, we found that Smad3 enhances Pdcd-1 transcription by binding to its proximal promoter region. Finally, a PD-1hi subset in Smad3-deficient CD8+ TILs was significantly decreased compared to wild-type T cells in a murine model of melanoma in association with enhanced anti-tumor function. In addition to TGF-b1’s previously known effects on T cell function, our findings suggest that TGF-b1 mediates suppression via PD-1 upregulation in the tumor microenvironment. Thus, Smad3 may represent an additional target in therapeutic modulation of PD-1.