TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance

By Dori A. Thomas, J. Massagué. 2005

1,332 citations recorded by the source corpus.

Summary Tumors escape from immune surveillance by producing the immunosuppressive cytokine TGF-β. However, the mechanism by which TGF-β inhibits T cell-mediated tumor clearance in vivo is unknown. We demonstrate that TGF-β acts on cytotoxic T lymphocytes (CTLs) to specifically inhibit the expression of five cytolytic gene products—namely, perforin, granzyme A, granzyme B, Fas ligand, and interferon γ—which are collectively responsible for CTL-mediated tumor cytotoxicity. Repression of granzyme B and interferon-γ involves binding of TGF-β-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-β/Smad pathway. Neutralization of systemic TGF-β in mice enables tumor clearance with restoration of cytotoxic gene expression in antigen-specific CTLs in vivo. We suggest that TGF-β suppresses CTL function in vivo through an anticytotoxic program of transcriptional repression.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/04f71b8962c1e9a5ef1a2f64e8cbe90a3ced8a72

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Citations in the corpus

Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy (2019, background): “As described above, αSMA+ CAFs are an important cellular source of TGF-β, which inhibits CD8+ T cell cytotoxic function by reducing the expression of perforin, granzymes A/B, FASL (FAS ligand), and IFN-γ[14, 76].”
Immunosuppressive strategies that are mediated by tumor cells. (2007, background): “Most recently, Thomas and Massague demonstrated that TGF-β acts on CTLs to specifically repress the expression of different cytolytic gene products; namely perforin, granzyme A, granzyme B, Fas ligand (Fas L), and IFN-γ, which are collectively responsible for CTL-mediated tumor cytotoxicity (71).”
The logic of TGFβ signaling (2006, background): “their tumor fighting capacity, allowing unfettered tumor growth [94] (Fig.”
Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. (2007, background): “However, it is important to note that TGF-b can influence the expression of perforin and granzymes, thereby altering the function of cytotoxic lymphocytes (Thomas and Massague, 2005).”
Next generation of immune checkpoint therapy in cancer: new developments and challenges (2018, background): “Although this pathway is able to control early-stage tumors by promoting cell cycle arrest and apoptosis, in advanced stages, it allows for tumor evasion by suppressing cytotoxic T cells and promotes cancer cell proliferation, invasion, and metastases, a functional switch known as the “TGF-β paradox”
TGFβ in Cancer (2008, background): “TGFβ acting through the Smad pathway in CD8+ CTLs represses the production of cytolytic factors including the pore-forming protein perforin, the caspase-activating secreted factors granzyme A and B, and the proapoptotic cytokines Fas-ligand and IFN-γ (Thomas and Massagué, 2005).”
CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review (2018, background): “TGF‐β would do this through inhibition of the expressions for cytolytic gene products from CTLs, including granzymes A and B, perforin, FasL, and IFN‐γ. Tumor cytotoxicity of CTLs is mediated through the function of these genes (Thomas & Massagué, 2005).”
TGF-beta: a master of all T cell trades. (2008, neutral): “(Thomas and Massague, 2005).”