Abstract 2936: In situ antitumor immunotherapy with pharmacological blockade of MFG-E8 and chemotherapy against solid and hematological tumors

Abstract

Abstract The conventional anticancer strategies, such as chemotherapy and radiotherapy, induce the tumor cell death, which would theoretically become the source of tumor antigens to be recognized in situ by the immune system. However, most of the cytotoxic therapies rarely induce the immunological responses potent enough to cause obvious tumor destruction in the actual clinical settings. This discrepancy might be caused by the tumor evasion systems, which restrain the induction of host immune responses. Thus, the therapeutic efficacy of various anticancer agents could be improved if the novel strategies are found to reverse molecular machineries of tumor-mediated immune evasion. Milk-fat globule EGF-8 (MFG-E8) has been known to maintain tissue homeostasis in multiple aspects; regulating the phagocytosis of apoptotic cells, breast tissue morphogenesis, intestinal epithelium homeostasis and angiogenesis. Here we have shown that the therapeutic interference of MFG-E8 synergistically potentiates antitumor activities of various cytotoxic and target therapies, and radiotherapy, against various murine tumors. These antitumor activities relied on the induction of the potent and specific antitumor immune responses in situ. The MFG-E8 blockade triggered infiltration and activation of dendritic cells at the tumor sites, where apoptotic cells were made available with cytotoxic treatments, resulting in the potent antitumor effector T cell activation and inhibition of Foxp3+Treg cell function. Furthermore, the administration of anti-MFG-E8 antibodies switches the receptor for MFG-E8-mediated tumor cell ingestion from integrins αvβ3 to activating FcγRI/III receptors in dendritic cell recognition of tumor cells, augmenting dendritic cell-mediated cross-priming of tumor-specific T cells. These findings demonstrated that the blockade of MFG-E8, one of the key negative regulators to restrain immune responses against the dying cells, would be a novel strategy to improve durable antitumor responses by various anticancer therapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2936.