Abstract 2556: The protective role of mast cells against neuroendocrine prostate cancer depends on the release of cytokines mediated by intracellular osteopontin

Abstract

Abstract Fatal neuroendocrine prostate cancer (NEPC) often emerges in patients relapsing after hormone therapies. Besides, de novo NEPC can rarely occur in treatment-naïve patients. Treatment-related and de-novo NEPC have different genomic alterations but share a common transcriptional profile. Investigating the tumor microenvironment, we recently found that mast cells (MCs) accumulate within hormone-sensitive prostate cancer favoring its growth, whereas are excluded by de-novo NEPC both in patients and in the transgenic TRAMP spontaneous mouse model. TRAMP mice backcrossed with MCs-deficient KitWsh mice showed increased frequency of de-novo NEPC. The frequency of de-novo NEPC similarly raised also in TRAMP mice deficient for the matricellular protein osteopontin (OPN). Reconstituting KitWsh-TRAMP mice with wild type, but not with OPN-deficient, MCs lowered the frequency of NEPC to that of untreated TRAMP mice. We found that MCs stain positive for OPN in tumor sections and in vitro cultures, but release a tiny amount of OPN in supernatants if compared to NEPC cells. Notably, OPN has both secreted (sOPN) and intracellular (iOPN) forms; the latter can bind to MyD88 and regulate the signaling downstream toll-like receptors (TLRs). In vitro, wild type, but not OPN-/- or MyD88-/-, MCs inhibited the proliferation of NEPC cells. Also, in silico analyses showed that genes related to inflammatory response and TLRs signaling are down regulated in human and murine NEPC.Our data suggest that TLRs/MyD88/iOPN-mediated pathways induce MCs to release factor(s) able to restrain NEPC. Further studies are required to molecularly dissect this novel function of MCs, to identify actionable targets against NEPC. Citation Format: Roberta Sulsenti, Barbara Frossi, Valeria Cancila, Claudia Enriquez, Renata Ferri, Sabina Sangaletti, Claudio Tripodo, Carlo Emilio Pucillo, Mario Paolo Colombo, Elena Jachetti. The protective role of mast cells against neuroendocrine prostate cancer depends on the release of cytokines mediated by intracellular osteopontin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2556.