Abstract A54: Ly6Chi inflammatory monocytes mediate tumor regression in a mouse model of spontaneously arising pancreatic ductal adenocarcinoma

Abstract

Abstract Macrophage infiltration into solid malignancies most often portends a poor prognosis. In pancreatic ductal adenocarcinoma (PDAC), macrophages dominate the leukocyte infiltrate with effector T lymphocytes remaining scarce. Strategies to restore productive immunosurveillance in PDAC have largely focused on inducing anti-tumor T cell immunity. However, we have previously shown in patients and a mouse model of PDAC that immune modulation with a CD40 agonist can induce macrophages to facilitate tumor regression. Thus, strategies that restore innate immunosurveillance may hold promise in the treatment of PDAC. To further investigate the role of macrophages as targets for anti-tumor immunotherapy, we utilized the KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) genetically engineered mouse model of PDAC. We previously reported a role for liposomal targeted macrophages in facilitating tumor regression induced with CD40 therapy. However, unexpectedly we found by immunohistochemistry that macrophages targeted by liposomes do not infiltrate PDAC tumors in response to CD40 therapy. This finding suggested a role for additional leukocyte subsets in mediating the anti-tumor effect. Using immunohistochemistry, we found that systemic CD40 activation induced the infiltration of Ly6C+ myeloid cells into KPC tumors. Based on this finding, we hypothesized that macrophages may regulate the infiltration of Ly6Chi inflammatory monocytes, which are the critical effector myeloid cells mobilized in the peripheral blood by CD40 agonist therapy. In support of this hypothesis, we found that tumor regression induced with a CD40 agonist was abrogated by treatment with the anti-Ly6C/Ly6G RB6-8C5 depleting antibody. Flow cytometric analysis of peripheral blood revealed that RB6-8C5 and liposomes target distinct myeloid subsets. Whereas RB6-8C5 was found to deplete Ly6ChiCCR2+ inflammatory monocytes, CEL depleted Ly6Cneg myeloid cells. Our findings suggest that CD40-induced tumor regression in PDAC is mediated by inflammatory monocytes which infiltrate tumor lesions under the regulation of extra-tumoral macrophages. Citation Format: Whitney L. Gladney, Graham M. Tooker, Gregory L. Beatty. Ly6Chi inflammatory monocytes mediate tumor regression in a mouse model of spontaneously arising pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A54.