title: Cell-intrinsic abrogation of TGF-β signaling delays but does not prevent dysfunction of self/tumor-specific CD8 T cells in a murine model of autochthonous prostate cancer.
abstract: 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.
authors.affiliation: Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98105, USA.
authors.forename: Cassie K
authors.initials: CK
authors.lastname: Chou
authors.forename: Andrea
authors.initials: A
authors.lastname: Schietinger
authors.forename: H Denny
authors.initials: HD
authors.lastname: Liggitt
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Tan
authors.forename: Sarah
authors.initials: S
authors.lastname: Funk
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Ratliff
authors.forename: Norman M
authors.initials: NM
authors.lastname: Greenberg
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D016212:Transforming Growth Factor beta