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Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells

Abstract

Despite the existence of tumor-specific antigens and demonstrated presence of tumor-specific immune cells, the majority of tumors manage to avoid immune-mediated destruction. Various mechanisms have been suggested for tumor evasion from immune response. One such mechanism is thought to be mediated by transforming growth factor-β (TGF-β), an immunosuppressive cytokine found at the site of most tumors. We demonstrate here that T-cell–specific blockade of TGF-β signaling allows the generation of an immune response capable of eradicating tumors in mice challenged with live tumor cells. In addition, we provide mechanisms through which abrogation of TGF-β signaling leads to the enhancement of anti-tumor immunity. Our data indicate that T-cell–specific blockade of TGF-β signaling has strong therapeutic potential to shift the balance of the immune response in favor of anti-tumor immunity.

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Figure 1: Blockade of TGF-β signaling in T cells renders mice resistant to tumor challenge.
Figure 2: In vivo generation of tumor-specific CD8+ CTLs in the absence of TGF-β signaling in T cells.
Figure 3: Requirement for TGF-β blockade in T cells for tumor eradication.
Figure 4: Blockade of TGF-β signaling in T cells allows for the selective expansion of tumor-specific CD8+ T cells.

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Acknowledgements

We thank R.W. Dutton and A. Garen for gifts of tumor cell lines; J. Miller and D. Butkus for technical help; and F. Manzo for help with manuscript preparation.

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Correspondence to Richard A. Flavell.

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Gorelik, L., Flavell, R. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nat Med 7, 1118–1122 (2001). https://doi.org/10.1038/nm1001-1118

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