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.

Concurrent Allorecognition Has a Limited Impact on Posttransplant Vaccination

“…2B, 2C). This donor sex-independent expansion was also found in tumor-bearing TRAMP mice (26) and most likely reflects the ability of the cells to proliferate in the lymphopenic environment (35). Indeed, it was similarly observed upon cell infusion in female mice preconditioned by total body irradiation, reported to favor donor cell engraftment (36), and not in nonpreconditioned control ones (data not shown).…”

“…Syngeneic and allogeneic peptide-pulsed DCs elicit comparable peptide-specific CD8 + T cell priming Tumor-specific vaccination by peptide-pulsed DC following allogeneic hematopoietic cell transplantation is critical for prolonging disease-free survival (26) and optimizing tumor-specific T cell priming (R. Hess Michelini, T. Manzo, M. Freschi, V. Basso, M. Rocchi, E. Simpson, M. Bellone, and A. Mondino, submitted for publication). Whether the immunogenicity of DCbased vaccines is influenced by concomitant alloreactive T cell responses remained to be determined.…”

“…Two weeks after HSCT, ∼50% of bone marrow-derived cells were of donor origin (data not shown and Ref. 26). Mice then received a DLI of 6 3 10 7 splenocytes from congenic CD45.1 + male (mDLI) or female donors (fDLI).…”

“…Then, cells were surface stained, fixed, and analyzed for intracellular cytokine staining as described previously (26). Unless otherwise indicated, cytokine production in the absence of stimulation (Nil) was considered as background release and subtracted from values obtained by the specific peptides.…”

“…We choose this particular setting as we have recently reported that tumorspecific vaccination promotes optimal tumor-specific T cell priming and disease-free survival in mice undergoing nonmyeloablative allogeneic transplantation (26). This previous study mainly focused on alloresponse to Y-encoded H Ags and provided the proof of principle that minor H antigen-and tumor-specific T cells cooperate for prostate cancer eradication but did not determine whether alloreactive T cell responses would influence immunogenicity if peptides were presented on allogeneic rather than syngeneic dendritic cells (DC).…”