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Vaccine-instructed intratumoral IFN-γ enables regression of autochthonous mouse prostate cancer in allogeneic T cell transplantation

Authors

  • R. Hess Michelini
  • T. Manzo
  • T. Sturmheit
  • V. Basso
  • M. Rocchi
  • M. Freschi
  • J.J. Listopad
  • T. Blankenstein
  • M. Bellone
  • A. Mondino

Journal

  • Cancer Research

Citation

  • Canc Res 73 (15): 4641-4652

Abstract

  • Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematological 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 non-myeloablative MHC-matched, single Y chromosome-encoded or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here we report that tumor-directed 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-{gamma}+ tumor-directed effector cells in secondary lymphoid organs and also for IFN-{gamma}+ upregulation at the tumor site, which in turn instructed local expression of pro-inflammatory chemokines and intratumoral recruitment of donor-derived T cells for disease regression. Omitting vaccination, transplanting IFN-{gamma} deficient donor T cells or depleting alloreactive T cells all compromised intratumoral IFN-{gamma}-driven inflammation and lymphocyte infiltration, abolishing anti-tumor responses and therapeutic efficacy of the combined approach. Our findings argue that post-transplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation.


DOI

doi:10.1158/0008-5472.CAN-12-3464