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Medicine Matters Home Article of the Week TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer

TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer

T cells are an important arm of the immune system that controls infections and tumor growth. When T cells fail, viruses and tumors persist and we see chronic infection or malignancies ensue. There is often high-level expression of a molecule that inhibits T cell function, programmed death-1 or PD-1 on tumor or chronic virus (HIV, HCV and HBV) T cells. When there is high-level expression of PD-1, T cells don't do their jobs and tumors and chronic viral infections are allowed to persist. There are newly FDA approved treatments for cancer patients that block the pathway we studied with the goal of activating T cells to kill tumor cells. This has been a big advance in melanoma, some types of lung cancer and renal cancer. However, they don't work in more than 40% of patients with those cancers. Part of what we didn't know that might help us improve therapy is what drives high-level production of PD-1. Our paper defines an additional important mechanism for increasing PD-1 when T cells recognize virally infected or tumor cells. We hope this will allow improvements in the therapy for cancers and potentially for HIV cure, for which blockade of PD-1 is also being investigated. 

ARTICLE: TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer

AUTHORS: Benjamin V. Park, Zachary T. Freeman, Ali Ghasemzadeh, Michael A. Chattergoon, Alleluiah Rutebemberwa, Jordana Steigner, Matthew E. Winter, Thanh V. Huynh, Suzanne M.Sebald, Se-Jin Lee, Fan Pan, Drew M. Pardoll and Andrea L. Cox

JOURNAL: Cancer Discov. 2016 Dec;6(12):1366-1381. Epub 2016 Sep 28.


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 TGFβ1 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 TGFβ1's previously known effects on T-cell function, our findings suggest that TGFβ1 mediates T-cell suppression via PD-1 upregulation in the tumor microenvironment (TME). They highlight bidirectional cross-talk between effector TILs and TGFβ-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 TGFβ and demonstrate that TGFβ1 allows tumors to evade host immune responses in part through enhanced SMAD3-mediated PD-1 expression on TILs.

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Kelsey Bennett