Macrophage Ron signaling regulates the antitumor immune response in prostate cancer - Abstract
Nearly 30,000 men die from prostate cancer (PCa) in the United States each year due to advanced and
metastatic disease. Furthermore, the incidence of advanced and metastatic disease has increased by 72%
within the last decade. Mainstay treatments fail to effectively treat distant and aggressive disease, however
targeting the interaction between the immune system and PCa has emerged as a promising therapeutic
strategy to overcome these failures. The leading immunotherapy agents, Sipuleucel-T and checkpoint
blockade inhibitors, are approved or in clinical trials to treat metastatic castration-resistant prostate cancer
(mCRPC), however the clinical performance of these agents has been underwhelming. Thus, there is a
pronounced need for more effective immunotherapeutic strategies to treat advanced PCa.
We have compelling preliminary data suggesting that the cell surface receptor Ron tyrosine kinase is a
key regulator of antitumor immunity. Our previous studies established the Ron receptor in macrophages as a
critical promoter of prostate tumor growth, thus we sought to elucidate the mechanistic roles of macrophage
Ron signaling in PCa. We observe for the first time that loss of Ron signaling in macrophages significantly
reduces prostate tumor growth in an autochthonous mouse model. Antibody depletion of CD8+, but not CD4+,
T cells restored tumor growth, suggesting Ron expression in macrophages dampens CD8+ T cell function as a
host immune escape mechanism. Tumors from mice with myeloid-specific Ron loss exhibit increased
apoptosis concurrent with enhanced macrophage infiltration. Further, in vitro experiments revealed Ron-
deficient macrophages produce more nitric oxide (NO) and induce increased tumor cell apoptosis in direct co-
culture compared to wild-type macrophages. Taken together, this data suggests increased tumor infiltration of
Ron-deficient macrophages synergizes with increased NO production to enhance NO-mediated tumoricidal
activity. Collectively, these findings suggest that loss of Ron in macrophages stimulates direct and indirect
mechanisms of antitumor immunity to reduce prostate tumor growth. Furthermore, our preliminary data
suggests vaccination with Ron-deficient macrophages is sufficient to reduce tumor growth in vivo. Taken
together, we hypothesize that loss of Ron in macrophages reinvigorates the antitumor immune response by
increasing CD8+ T cell recruitment and activation and enhancing macrophage-mediated tumor cytotoxicity. To
test this hypothesis, the following aims are proposed: (1) Determine the mechanism by which macrophage Ron
dampens CD8+ T cell functions and (2) Define the role of Ron in impairing macrophage-mediated cytotoxicity.
Collectively, these studies will dissect the mechanisms by which macrophage Ron attenuates the
antitumor immune response to promote PCa and provide a novel immunotherapeutic strategy to treat PCa.
