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Macrophage Ron signaling regulates the antitumor immune response in prostate cancer

Award Number: F31CA228425
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2020

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Research Manpower	001	2	4/22/2022	NON-COMPETING CONTINUATION	-$6,005
2022	2020	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Research Manpower	002	2	9/29/2022	NON-COMPETING CONTINUATION	$6,005
2022	2018	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Research Manpower	000	1	4/22/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $34,101 )
2020	2020	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Research Manpower	001	2	2/14/2020	NON-COMPETING CONTINUATION	$336
2020	2020	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Research Manpower	000	2	12/2/2019	NON-COMPETING CONTINUATION	$33,765
														Subtotal = $34,101

Issue Date FY: 2018 ( Subtotal = $41,545 )
2018	2018	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Research Manpower	000	1	9/17/2018	NEW	$41,545
														Subtotal = $41,545

Grand Total All Awards = $75,646

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Macrophage Ron signaling regulates the antitumor immune response in prostate cancer

Award Number: F31CA228425

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2020

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