| First Author | Park BV | Year | 2016 |
| Journal | Cancer Discov | Volume | 6 |
| Issue | 12 | Pages | 1366-1381 |
| PubMed ID | 27683557 | Mgi Jnum | J:237845 |
| Mgi Id | MGI:5817277 | Doi | 10.1158/2159-8290.CD-15-1347 |
| Citation | Park BV, et al. (2016) TGFbeta1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer. Cancer Discov 6(12):1366-1381 |
| abstractText | Programmed death-1 (PD-1) is a coinhibitory receptor that downregulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TILs have not been fully investigated. We demonstrate that TGFbeta1 enhances antigen-induced PD-1 expression through SMAD3-dependent, SMAD2-independent transcriptional activation in T cells in vitro and in TILs in vivo The PD-1hi subset seen in CD8+ TILs is absent in Smad3-deficient tumor-specific CD8+ TILs, resulting in enhanced cytokine production by TILs and in draining lymph nodes and antitumor activity. In addition to TGFbeta1's previously known effects on T-cell function, our findings suggest that TGFbeta1 mediates T-cell suppression via PD-1 upregulation in the tumor microenvironment (TME). They highlight bidirectional cross-talk between effector TILs and TGFbeta-producing cells that upregulates multiple components of the PD-1 signaling pathway to inhibit antitumor immunity. SIGNIFICANCE: Engagement of the coinhibitory receptor PD-1 or its ligand, PD-L1, dramatically inhibits the antitumor function of TILs within the TME. Our findings represent a novel immunosuppressive function of TGFbeta and demonstrate that TGFbeta1 allows tumors to evade host immune responses in part through enhanced SMAD3-mediated PD-1 expression on TILs. Cancer Discov; 6(12); 1366-81. (c)2016 AACRThis article is highlighted in the In This Issue feature, p. 1293. |
