Abstract 4054: Mast cells contribute to T cell tolerance against prostate cancer- associated antigens favoring tumor growth

Abstract

Abstract Treatments for hormone refractory and metastatic prostate cancer (PC) still remain palliative. Also tumor specific vaccinations when tested in the clinical setting showed results lower than expected. A major limitation to active immunotherapy relies on mechanisms of tolerance adopted by the tumor. Indeed, an immunosuppressive environment is established in PC patients, as well as in the TRAMP mouse model of PC, in which peripheral T cell tolerance to the tumor-associated antigen Tag is acquired early during neoplastic transformation, with mechanisms that still need to be fully clarified. Mast cells (MCs) have been described to mediate immunological tolerance in transplantation and in several disease models, including cancer. We have demonstrated their involvement in early stage of PC development. Therefore, we investigated whether immunosuppression is part of their supporting adenocarcinoma outgrowth in TRAMP mice. We crossed TRAMP mice with KitWsh mice, genetically lacking MCs, and followed tumor growth and Tag-specific CD8+ T cells response after immunization, measured as in vivo lytic activity or ex vivo cytokine production. MCs depletion restrained adenocarcinoma growth in about 70% of mice that at 30 weeks of age only showed evidences of intraepithelial neoplasia or local in situ well-differentiated adenocarcinoma. These lesions were much different from those raised in MCs-sufficient age-matched TRAMP counterparts that developed poor-differentiated multifocal invasive carcinoma. Notably, reduced tumor onset and aggressiveness correlated with improved immune surveillance. Indeed, 16 weeks old KitWsh-TRAMP mice matched for the size of prostatic lesions and for Tag expression, were able to mount a Tag-specific CTL response, whereas their TRAMP counterparts were tolerant. Reconstitution of KitWsh-TRAMP with bone marrow-derived MCs restored complete T cell tolerance. Interestingly, treatment of TRAMP mice with Cromolyn, a compound that inhibit MCs degranulation, had no effect on Tag-specific immune response while partially inhibited tumor growth. These results suggest that independent mechanisms may regulate local immunosuppression and tumor promotion by MCs. They also hint that surface receptors, rather than soluble mediators, are involved in MCs-mediated T cell tolerance. MCs contribute to the maintenance of an immunosuppressive environment, favoring the growth of well-differentiated prostate adenocarcinoma. This open the way for the identification of new therapeutic approaches in PC, aimed at coupling MCs targeting with other immunotherapeutic strategies. Citation Format: Elena Jachetti, Alice Rigoni, Lucia Bongiovanni, Claudio Tripodo, Mario P. Colombo. Mast cells contribute to T cell tolerance against prostate cancer- associated antigens favoring tumor growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4054. doi:10.1158/1538-7445.AM2015-4054