title: Vaccine-instructed intratumoral IFN-γ enables regression of autochthonous mouse prostate cancer in allogeneic T-cell transplantation.
abstract: Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematologic malignancies, but the basis for this synergy is not understood to the degree where such approaches could be effective for treating solid tumors. We investigated this issue in a transgenic mouse model of prostate cancer treated by transplantation of a nonmyeloablative MHC-matched, single Y chromosome-encoded, or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here, we report that tumor-directed vaccination after allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion is essential for acute graft versus tumor responses, tumor regression, and prolonged survival. Vaccination proved essential for generation of CD8(+) IFN-γ(+) tumor-directed effector cells in secondary lymphoid organs and also for IFN-γ(+) upregulation at the tumor site, which in turn instructed local expression of proinflammatory chemokines and intratumoral recruitment of donor-derived T cells for disease regression. Omitting vaccination, transplanting IFN-γ-deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-γ-driven inflammation and lymphocyte infiltration, abolishing antitumor responses and therapeutic efficacy of the combined approach. Our findings argue that posttransplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation.
authors.affiliation: Lymphocyte Activation Unit, Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Disease, Department of Pathology, San Raffaele Scientific Institute; Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Hess Michelini
authors.forename: Teresa
authors.initials: T
authors.lastname: Manzo
authors.forename: Tabea
authors.initials: T
authors.lastname: Sturmheit
authors.forename: Veronica
authors.initials: V
authors.lastname: Basso
authors.forename: Martina
authors.initials: M
authors.lastname: Rocchi
authors.forename: Massimo
authors.initials: M
authors.lastname: Freschi
authors.forename: Joanna
authors.initials: J
authors.lastname: Listopad
authors.forename: Thomas
authors.initials: T
authors.lastname: Blankenstein
authors.forename: Matteo
authors.initials: M
authors.lastname: Bellone
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: D019496:Cancer Vaccines; D007371:Interferon-gamma