Concomitant tumor and minor histocompatibility antigen-specific immunity initiate rejection and maintain remission from established spontaneous solid tumors.
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.
Hess Michelini
Rodrigo
R
Lymphocyte Activation Unit, Cellular Immunology Unit, Pathology Unit, Experimental Hematology, San Raffaele Scientific Institute, and Universita Vita-Salute San Raffaele, Milan, Italy.
Freschi
Massimo
M
Manzo
Teresa
T
Jachetti
Elena
E
Degl'Innocenti
Elena
E
Grioni
Matteo
M
Basso
Veronica
V
Bonini
Chiara
C
Simpson
Elizabeth
E
Mondino
Anna
A
Bellone
Matteo
M
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*
D000942:Antigens, Bacterial; D019496:Cancer Vaccines; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; C022863:H antigen