Abstract 4962: Metabolic rewiring of macrophages by CpG stimulates anti-tumor activity that overrides CD47-resistance in pancreatic cancer

Abstract

Abstract Although macrophages commonly support cancer growth, they can be induced with anti-tumor functions - such as the ability to phagocytose and kill tumor cells. This activity is governed by stimulatory as well as inhibitory signals (e.g. CD47). The role of central carbon metabolism in determining macrophage function, however, remains poorly understood. Here, we identify CpG-activated changes in the metabolism of macrophages to be a major determinant of their phagocytic and anti-tumor capabilities, including the ability to overcome inhibitory CD47 expressed by tumor cells. In a fully syngeneic model of murine pancreatic ductal adenocarcinoma (PDAC), systemic delivery of CpG re-directed macrophages to mediate anti-tumor activity against PDAC tumor cells independent of CD47 expressed by tumor cells. The anti-tumor potential stimulated by CpG was not associated with polarization of macrophages toward classical M1 or M2 phenotypes, but rather was dependent on a hybrid state of metabolic features found in M1 and M2 macrophages. These metabolic changes required shunting of tricarboxylic acid (TCA) cycle intermediates for de novo biosynthesis of lipids and elevated fatty acid oxidation (FAO) that was supported by glutamine anaplerosis. Coordination of these processes by carnitine palmitoyltransferase 1A (CPT1A) and ATP citrate lyase (ACLY) supported the ability of macrophages to bypass the CD47 inhibitory pathway and mediate anti-tumor functions. Our findings underscore a novel role for the metabolic state of macrophages in overriding barriers to anti-tumor activity, and reveal potential targets that may enhance CD47-based therapies. Citation Format: Mingen Liu, Roddy S. O'Connor, Sophie Trefely, Nathaniel W. Snyder, Gregory L. Beatty. Metabolic rewiring of macrophages by CpG stimulates anti-tumor activity that overrides CD47-resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4962.