Microenvironment and Immunology Myeloid-Specific Expression of Ron Receptor Kinase Promotes Prostate Tumor Growth

Ron receptor kinase (MST1R) is important in promoting epithelial tumorigenesis, but the potential contributions of its specific expression in stromal cells have not been examined. Herein, we show that the Ron receptor is expressed inmouse and human stromal cells of the prostate tumormicroenvironment. To test the significance of stromal Ron expression, prostate cancer cells were orthotopically implanted into the prostates of either wild-type or Ron tyrosine kinase deficient (TK / ; Mst1r / ) hosts. In TK / hosts, prostate cancer cell growth was significantly reduced as compared with tumor growth in TKþ/þ hosts. Prostate tumors in TK / hosts exhibited an increase in tumor cell apoptosis, macrophage infiltration and altered cytokine expression. Reciprocal bone marrow transplantation studies and myeloid cell–specific ablation of Ron showed that loss of Ron in myeloid cells is sufficient to inhibit prostate cancer cell growth. Interestingly, depletion of CD8þ T cells, but not CD4þ T cells, was able to restore prostate tumor growth in hosts devoid of myeloid-specific Ron expression. These studies show a critical role for the Ron receptor in the tumor microenvironment, whereby Ron loss in tumorassociatedmacrophages inhibits prostate cancer cell growth, at least in part, by derepressing the activity of CD8þ T cells. Cancer Res; 73(6); 1752–63. 2012 AACR.