title: Whole-body irradiation increases the magnitude and persistence of adoptively transferred T cells associated with tumor regression in a mouse model of prostate cancer.
abstract: Adoptive immunotherapy has demonstrated efficacy in a subset of clinical and preclinical studies, but the T cells used for therapy often are rendered rapidly nonfunctional in tumor-bearing hosts. Recent evidence indicates that prostate cancer can be susceptible to immunotherapy, but most studies using autochthonous tumor models demonstrate only short-lived T-cell responses in the tolerogenic prostate microenvironment. Here, we assessed the efficacy of sublethal whole-body irradiation (WBI) to enhance the magnitude and duration of adoptively transferred CD8(+) T cells in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We demonstrate that WBI promoted high-level accumulation of granzyme B (GzB, Gzmb)-expressing donor T cells both in lymphoid organs and in the prostate of TRAMP mice. Donor T cells remained responsive to vaccination in irradiated recipients, but a single round of WBI-enhanced adoptive immunotherapy failed to affect significantly the existing disease. Addition of a second round of immunotherapy promoted regression of established disease in half of the treated mice, with no progression observed. Regression was associated with long-term persistence of effector/memory phenotype CD8(+) donor cells. Administration of the second round of adoptive immunotherapy led to reacquisition of GzB expression by persistent T cells from the first transfer. These results indicate that WBI conditioning amplifies tumor-specific T cells in the TRAMP prostate and lymphoid tissue, and suggest that the initial treatment alters the tolerogenic microenvironment to increase antitumor activity by a second wave of donor cells.
authors.affiliation: Departments of Microbiology and Immunology.
authors.forename: Lindsay K
authors.initials: LK
authors.lastname: Ward-Kavanagh
authors.affiliation: Public Health Sciences, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.
authors.forename: Junjia
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Comparative Medicine, and Pathology, Penn State Hershey College of Medicine; and.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.affiliation: Departments of Microbiology and Immunology, Penn State Hershey Cancer Institute, Hershey, Pennsylvania tschell@hmc.psu.edu.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Schell
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D016219:Immunotherapy, Adoptive; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D013154:Spleen / Q000276:immunology; D014916:Whole-Body Irradiation