Abstract 2676: Role of the RON kinase in the regulation of the antitumor immune response in pancreatic cancer
Authors: Alex Cazes, Michele L. Babicky, Jeffery Chakedis, Divya Sood, Dawn Jaquish, Andrew M. Lowy
Journal: Cancer Research (2017)

Abstract RON is a cell-surface receptor for the macrophage-stimulating protein expressed in tissue-resident macrophages and overexpressed in multiple epithelial neoplasms including pancreatic cancer. Our laboratory recently found that RON serves to mediate pancreatic duct carcinogenesis initiated by KRAS. We demonstrated that RON overexpression in the pancreas results in more rapid local and metastatic progression ultimately associated with decreased survival. We also discovered profound changes in the immunophenotype within the tumor microenvironment associated with RON expression. We notably established that RON expression drives the polarization of tumor-associated macrophages into an alternative, pro-tumorigenic state. We hypothesize that these unique activities help to shape the immunosuppressive milieu of the pancreatic cancer microenvironment and that RON directed therapy has the potential to serve as a novel immunomodulatory strategy in this disease. The aim of this work is to define how RON signaling contributes to shaping the pancreatic cancer microenvironment. In order to further interrogate the role of RON during pancreatic carcinogenesis, we bred kinase-dead RON mice (KD) to Pdx1-cre/LSL-KRASG12D mice. We observed a significant delay in the onset of pancreatic neoplasia and a significant decrease in tumor weight. The absence of functional RON kinase markedly reduced trafficking of CD11b+ cells to the pancreas and immunophenotyping in tumors showed a clear reduction of alternatively polarized macrophages when compared to RON overexpression or KRAS mutation alone. Because RON is expressed in both epithelial and stromal cell populations, we further sought to dissect the relevance of RON function to tumor growth within these cellular compartments. We performed orthotopic injections of organoïd-3D cells derived from tumors of KPC mice (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre). These cells were injected in wild type (WT) or RON KD mice. Preliminary results show that tumor growth is impaired in KD mice, suggesting that RON activity in the host microenvironment influence tumor growth. In order to identify all immune populations regulated by RON, we will conduct an exhaustive immunophenotyping of murine pancreatic tumors. A transcriptomic analysis will then be conducted on selected cell populations to better define the molecular mechanisms associated with the RON regulation. Finally, given the effect of RON signaling on macrophage polarization, we will also dissect the effects of RON signaling from bone marrow derived myeloid cells versus resident tissue macrophages. Preliminary results and future experiments will significantly narrow the gap in our understanding of how RON signaling contributes to shaping the pancreatic cancer chimera and therefore how RON-directed therapies could be most successfully utilized to the benefit of those afflicted with this most deadly disease Citation Format: Alex Cazes, Michele L. Babicky, Jeffery Chakedis, Divya Sood, Dawn Jaquish, Andrew M. Lowy. Role of the RON kinase in the regulation of the antitumor immune response in pancreatic cancer [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 2676. doi:10.1158/1538-7445.AM2017-2676