Abstract 3540: Prostate cancer-infiltrating mast cells suppress anti-tumor immunity through a TGFβ and IL-13 dependent mechanism

Abstract

Abstract Immune suppression is a major obstacle in the design of successful immune-based therapies for cancer. Using an experimental model of prostate cancer, we previously demonstrated the rapid induction of tolerance and suppressive activity in adoptively transferred tumor antigen-specific cytotoxic T cells. The mechanism of this tolerance induction involved T cell interactions with tumor-associated dendritic cells (TADCs) which express elevated levels of the forkhead box protein, FOXO3. We now propose a mechanism by which tumor-infiltrating mast cells exert immune suppressive activity on both T cells and DCs. Mast cells were identified as approximately 30% of the total CD45+ tumor-infiltrating leukocytes and were capable of degranulation and promoting immune suppression. Purified tumor-associated mast cells (TA-MC) spontaneously secreted IL-13 and TGF-β which were further increased by FcαR cross-linking or LPS stimulation. The suppression of Ag-specific T cells and the development of tolerogenic DC were found to be dependent on TA-MC secretion of TGF-β and IL-13 during in vitro co-culture. Further, blocking IL-13 and TGF-β in vivo prevented the induction of DC tolerogenicity and the induction of T cell tolerance, which, in turn, resulted in reduced tumor burden. Our findings reveal novel mast cell-mediated mechanisms that favor immune tolerance over anti-tumor immunity and therefore provide promising targets for the enhancement of cancer immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3540. doi:1538-7445.AM2012-3540