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Immunity. 2014 Sep 18;41(3):427-439. doi: 10.1016/j.immuni.2014.08.012.

Transforming growth factor β-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression.

Author information

1
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
2
Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA.
3
Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA; Rena Rowan Breast Center, University of Pennsylvania, Philadelphia, PA 19104-1693, USA; Abramson Cancer Center Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-1693, USA.
4
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jrconejo@wistar.org.

Abstract

Tumor-reactive T cells become unresponsive in advanced tumors. Here we have characterized a common mechanism of T cell unresponsiveness in cancer driven by the upregulation of the transcription factor Forkhead box protein P1 (Foxp1), which prevents CD8⁺ T cells from proliferating and upregulating Granzyme-B and interferon-γ in response to tumor antigens. Accordingly, Foxp1-deficient lymphocytes induced rejection of incurable tumors and promoted protection against tumor rechallenge. Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8⁺ T cells in response to microenvironmental transforming growth factor-β (TGF-β), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-β-induced c-Jun transcriptional repression, which abrogated T cell activity. Our results unveil a fundamental mechanism of T cell unresponsiveness different from anergy or exhaustion, driven by TGF-β signaling on tumor-associated lymphocytes undergoing Foxp1-dependent transcriptional regulation.

PMID:
25238097
PMCID:
PMC4174366
DOI:
10.1016/j.immuni.2014.08.012
[Indexed for MEDLINE]
Free PMC Article

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