title: Concomitant tumor and minor histocompatibility antigen-specific immunity initiate rejection and maintain remission from established spontaneous solid tumors.
abstract: Nonmyeloablative hematopoietic cell transplantation can cure patients with hematologic malignancies but has reported limited success against solid tumors. This is possibly because of profound peripheral tolerance mechanisms and/or suboptimal tumor recognition by effector T lymphocytes. We report that in mice developing spontaneous prostate cancer, nonmyeloablative minor histocompatibility mismatched hematopoietic stem cell transplantation, and donor lymphocyte infusion of unmanipulated lymphocytes combined with posttransplant tumor-specific vaccination circumvents tumor-specific tolerance, allowing acute tumor rejection and the establishment of protective immunosurveillance. Although donor-derived tumor-specific T cells readily differentiated into effector cells and infiltrated the tumor soon after infusion, they were alone insufficient for tumor eradication, which instead required the concomitance of minor histocompatibiltiy antigen-specific CD8(+) T-cell responses. The establishment of protective immunosurveillance was best induced by posttransplant tumor-specific vaccination. Hence, these results provide the proof of principle that tumor-specific T-cell responses have to be harnessed together with minor histocompatibility responses and sustained by posttransplant tumor-specific vaccination to improve the efficacy of allotransplantion for the cure of solid tumors.
authors.affiliation: Lymphocyte Activation Unit, Cellular Immunology Unit, Pathology Unit, Experimental Hematology, San Raffaele Scientific Institute, and Universita Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Hess Michelini
authors.forename: Massimo
authors.initials: M
authors.lastname: Freschi
authors.forename: Teresa
authors.initials: T
authors.lastname: Manzo
authors.forename: Elena
authors.initials: E
authors.lastname: Jachetti
authors.forename: Elena
authors.initials: E
authors.lastname: Degl'Innocenti
authors.forename: Matteo
authors.initials: M
authors.lastname: Grioni
authors.forename: Veronica
authors.initials: V
authors.lastname: Basso
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
authors.forename: Matteo
authors.initials: M
authors.lastname: Bellone
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D018572:Disease-Free Survival; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D016219:Immunotherapy, Adoptive; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy*
chemical_list: D000942:Antigens, Bacterial; D019496:Cancer Vaccines; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; C022863:H antigen