Abstract 4621: Metabolic activation of macrophages by CpG stimulates anti-tumor activity and overcomes CD47-independent inhibition by tumor cells in pancreatic ductal adenocarcinoma

Abstract

Abstract Macrophages dominate the immune infiltrate present in pancreatic ductal adenocarcinoma (PDAC). Although tumor-infiltrating macrophages have the potential to mediate anti-tumor activity, they most commonly acquire an immunosuppressive role in cancer. We have found that CpG oligonucleotides - containing unmethylated cytosine-guanine motifs - potently induce macrophages to phagocytose PDAC cells and mediate anti-tumor effects. When delivered in vivo, in a fully immunocompetent murine model of PDAC, CpG increased the presence of macrophages within PDAC tumors and suppressed tumor outgrowth in a macrophage-dependent manner. Though CpG did not polarize macrophages toward classical anti-tumor (M1) or pro-tumor (M2) phenotypes, CpG treatment increased the basal rate of oxygen consumption in macrophages. Reversing this metabolic shift by inhibiting fatty acid oxidation abolished pro-phagocytic and anti-tumor effects by macrophages in vitro and in vivo. We investigated the impact of CpG in overcoming anti-phagocytic signals from CD47, a membrane protein overexpressed in multiple malignancies, including PDAC. While targeted knockout of CD47 in PDAC cells was not sufficient to activate in vitro phagocytosis by macrophages or anti-tumor effects in vivo, delivery of CpG potentiated anti-tumor and phagocytic activity that was independent of CD47 expression by tumor cells. However, the combination of CD47 loss in tumor cells and systemic CpG treatment enhanced the survival of tumor-bearing mice, indicating that disruption of CD47 can sensitize tumors to macrophage-directed immunotherapy. Together, our findings demonstrate a key role for cellular metabolism in directing the anti-tumor functions of macrophages and overcoming negative regulatory signals imposed by malignant cells. Citation Format: Mingen Liu, Gregory Beatty. Metabolic activation of macrophages by CpG stimulates anti-tumor activity and overcomes CD47-independent inhibition by tumor cells in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4621. doi:10.1158/1538-7445.AM2017-4621