TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer

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, Andrea L. Cox

Research output: Contribution to journalArticle

Abstract

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-1 hi 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.

Original languageEnglish (US)
Pages (from-to)1366-1381
Number of pages16
JournalCancer Discovery
Volume6
Issue number12
DOIs
StatePublished - Dec 1 2016

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T-Lymphocytes
Antigens
Neoplasms
Tumor Microenvironment
Up-Regulation
Tumor-Infiltrating Lymphocytes
Immunosuppressive Agents
Transcriptional Activation
Immunity
Down-Regulation
Lymph Nodes
Cytokines
Ligands
Viruses
Infection
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology

Cite this

Park, B. V., Freeman, Z. T., Ghasemzadeh, A., Chattergoon, M. A., Rutebemberwa, A., Steigner, J., ... Cox, A. L. (2016). TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discovery, 6(12), 1366-1381. DOI: 10.1158/2159-8290.CD-15-1347

TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. / Park, Benjamin V.; Freeman, Zachary T.; Ghasemzadeh, Ali; Chattergoon, Michael A.; Rutebemberwa, Alleluiah; Steigner, Jordana; Winter, Matthew E.; Huynh, Thanh V.; Sebald, Suzanne M.; Lee, Se Jin; Pan, Fan; Pardoll, Drew M.; Cox, Andrea L.

In: Cancer Discovery, Vol. 6, No. 12, 01.12.2016, p. 1366-1381.

Research output: Contribution to journalArticle

Park, BV, Freeman, ZT, Ghasemzadeh, A, Chattergoon, MA, Rutebemberwa, A, Steigner, J, Winter, ME, Huynh, TV, Sebald, SM, Lee, SJ, Pan, F, Pardoll, DM & Cox, AL 2016, 'TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer' Cancer Discovery, vol 6, no. 12, pp. 1366-1381. DOI: 10.1158/2159-8290.CD-15-1347
Park BV, Freeman ZT, Ghasemzadeh A, Chattergoon MA, Rutebemberwa A, Steigner J et al. TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discovery. 2016 Dec 1;6(12):1366-1381. Available from, DOI: 10.1158/2159-8290.CD-15-1347

Park, Benjamin V.; Freeman, Zachary T.; Ghasemzadeh, Ali; Chattergoon, Michael A.; Rutebemberwa, Alleluiah; Steigner, Jordana; Winter, Matthew E.; Huynh, Thanh V.; Sebald, Suzanne M.; Lee, Se Jin; Pan, Fan; Pardoll, Drew M.; Cox, Andrea L. / TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer.

In: Cancer Discovery, Vol. 6, No. 12, 01.12.2016, p. 1366-1381.

Research output: Contribution to journalArticle

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