TY - JOUR
T1 - Vaccine-instructed intratumoral IFN-g enables regression of autochthonous mouse prostate cancer in allogeneic T-cell transplantation
AU - Michelini, Rodrigo Hess
AU - Manzo, Teresa
AU - Sturmheit, Tabea
AU - Basso, Veronica
AU - Rocchi, Martina
AU - Freschi, Massimo
AU - Listopad, Joanna
AU - Blankenstein, Thomas
AU - Bellone, Matteo
AU - Mondino, Anna
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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 tumordirected 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-g+ tumor-directed effector cells in secondary lymphoid organs and also for IFN-g+ 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-g-deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-g-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.
AB - 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 tumordirected 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-g+ tumor-directed effector cells in secondary lymphoid organs and also for IFN-g+ 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-g-deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-g-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.
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U2 - 10.1158/0008-5472.CAN-12-3464
DO - 10.1158/0008-5472.CAN-12-3464
M3 - Article
C2 - 23749644
AN - SCOPUS:84881420066
SN - 0008-5472
VL - 73
SP - 4641
EP - 4652
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -