T Cell Surveillance of Oncogene-Induced Prostate Cancer Is Impeded by T Cell-Derived TGF-β1 Cytokine

Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Immunity (Impact Factor: 21.56). 07/2011; 35(1):123-34. DOI: 10.1016/j.immuni.2011.04.019
Source: PubMed


Tolerance induction in T cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-β is implicated in immunosuppression, but the cellular mechanism by which TGF-β induces T cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-β signaling in T cells from the tumor-draining lymph nodes. Blockade of TGF-β signaling in T cells enhanced tumor antigen-specific T cell responses and inhibited tumor development. Surprisingly, T cell- but not Treg cell-specific ablation of TGF-β1 was sufficient to augment T cell cytotoxic activity and blocked tumor growth and metastases. These findings reveal that T cell production of TGF-β1 is an essential requirement for tumors to evade immunosurveillance independent of TGF-β produced by tumors.

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Available from: Achim A Jungbluth
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    • "Conventional T cells also produce TGF-b. Interestingly , in some models, T cell-derived TGF-b (including TGF-b produced by Treg cells) is sufficient for antitumor T cell suppression , while ablation of TGF-b only in Treg cells has insignificant effects (Donkor et al., 2011). Furthermore, TGF-b can also suppress effector cytokines in antitumor CD8 + lymphocytes Immunity 41, 427–439, September 18, 2014 ª2014 Elsevier Inc. 427 (Ahmadzadeh and Rosenberg, 2005). "
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    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.
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    • "Tumor secretion of TGF-β1 is therefore conceptualized to dampen T cell reactivity at the tumor microenvironment where T cells are exposed to large quantities of TGF-β1 produced by tumor cells. Contrary to this view, we demonstrated in our recent studies that T cell-specific deletion of TGF-β1 protected mice against tumor growth and metastasis independent of TGF-β1 produced by tumor cells[18]. In Tgfb1f/n Cd4cre-TRAMP mice, we found that protective tumor immunity was associated with T cell differentiation into IFN-γ- and granzyme (Gzm)B-producing effectors in the tumor draining lymph nodes and prostate[18] in line with reports showing that TGF-β1 suppressess antitumor immunity by transcriptional repression of the CTL program including the expression of IFN-γ and GzmB[54]. "
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    ABSTRACT: During their development, tumors acquire multiple capabilities that enable them to proliferate, disseminate and evade immunosurveillance. A putative mechanism is through the production of the cytokine TGF-β1. We showed in our recent studies that T cell-produced TGF-β1 inhibits antitumor T cell responses to foster tumor growth raising the question of the precise function of TGF-β1 produced by tumor cells in tumor development. Here, using a transgenic model of mammary cancer, we report that deletion of TGF-β1 from tumor cells did not protect mice from tumor development. However, ablation of TGF-β1 from T cells significantly inhibited mammary tumor growth. Additionally, absence of TGF-β1 in T cells prevented tumors from advancing to higher pathological grades and further suppressed secondary tumor development in the lungs. These findings reveal T cells but not tumor cells as a critical source of TGF-β1 that promotes tumor development.
    Full-text · Article · Dec 2011 · Oncotarget

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