Abstract
Abstract In cancer, increased mobilization of inflammatory monocytes from the bone marrow into the peripheral blood correlates inversely with patient survival. Peripheral blood inflammatory monocytes, which express CCR2, are recruited to tumor tissue by the chemokine CCL2 where they then differentiate into macrophages and support tumor development, growth, and metastasis. While neutralization of CCL2 can block inflammatory monocyte recruitment and inhibit metastasis, this approach has recently been shown to be at risk for lethal outcomes if therapy is interrupted. An alternative approach to inhibiting inflammatory monocyte recruitment to tumors is to reprogram monocytes with anti-tumor activity. Using the KrasG12D/+; Trp53R172H/+; Pdx-1 Cre (KPC) genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC), we report that systemic immune activation induced with an agonist CD40 monoclonal antibody can redirect Gr-1+ inflammatory monocytes to infiltrate the tumor microenvironment and degrade tumor-associated fibrosis leading to tumor regression. Extra-tumoral macrophages were found to be necessary for mobilization of inflammatory monocytes from the bone marrow into the peripheral blood. In addition, systemic IFN-γ released in response to anti-CD40 therapy was necessary for reprogramming inflammatory monocytes with anti-tumor activity. Inflammatory monocytes responding to IFN-γ displayed a distinct matrix metalloproteinase gene expression profile necessary for selective degradation of extracellular matrix proteins, including type I collagen and fibronectin, which define fibrosis in PDAC. Therefore, although inflammatory monocytes are commonly associated with pro-tumor activity, our findings demonstrate that they can also be reprogrammed with potent anti-tumor properties. Citation Format: Kristen B. Long, Whitney L. Gladney, Graham M. Tooker, Gregory L. Beatty. Reprogramming inflammatory monocytes to mediate anti-tumor activity in pancreatic carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-204. doi:10.1158/1538-7445.AM2015-LB-204
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