Concomitant Tumor and Minor Histocompatibility Antigen-Specific Immunity Initiate Rejection and Maintain Remission from Established Spontaneous Solid Tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-05, Vol.70 (9), p.3505-3514
• Main Authors: HESS MICHELINI, Rodrigo, FRESCHI, Massimo, BELLONE, Matteo, MANZO, Teresa, JACHETTI, Elena, DEGL'INNOCENTI, Elena, GRIONI, Matteo, BASSO, Veronica, BONINI, Chiara, SIMPSON, Elizabeth, MONDINO, Anna
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Bacterial - immunology; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; CD8-Positive T-Lymphocytes - immunology; Disease-Free Survival; Epitopes; Epitopes, T-Lymphocyte - immunology; Female; Hematopoietic Stem Cell Transplantation; Immunotherapy, Adoptive; Lymphocyte Transfusion; Lymphocytes - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Prostatic Neoplasms - immunology; Prostatic Neoplasms - therapy; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-4253

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.