Adoptive T cell therapy (ACT) for the treatment of established cancers is actively being pursued in clinical trials.
However, poor in vivo persistence and maintenance of antitumor activity of transferred T cells remain major problems. TGF-β is a potent immunosuppressive cytokine that is often expressed at high levels within the tumor microenvironment, potentially limiting T cell-mediated antitumor activity. In this study, we used a model of autochthonous murine prostate cancer to evaluate the effect of cell-intrinsic abrogation of TGF-β signaling in self/tumor-specific CD8 T cells used in ACT to target the tumor in situ. We found that persistence and antitumor activity of adoptively transferred effector T cells deficient in TGF-β signaling were significantly improved in the cancerous prostate. However, over time, despite persistence in peripheral lymphoid organs, the numbers of transferred cells in the prostate decreased and the residual prostate-infiltrating T cells were no longer functional. These findings reveal that TGF-β negatively regulates the accumulation and effector function of transferred self/tumor-specific CD8 T cells and highlight that, when targeting a tumor Ag that is also expressed as a self-protein, additional substantive obstacles are operative within the tumor microenvironment, potentially hampering the success of ACT for solid tumors.
Written by:
Chou CK, Schietinger A, Liggitt HD, Tan X, Funk S, Freeman GJ, Ratliff TL, Greenberg NM, Greenberg PD Are you the author?
Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98105
Reference: J Immunol. 2012 Oct 15;189(8):3936-46
doi: 10.4049/jimmunol.1201415
PubMed Abstract
PMID: 22984076
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