Wednesday, December 17, 2025 12/17/2025

Ethnicity-determined T cell responses and GARP/TGFbeta1 signaling in prostate cancer

Award Number: R01CA260351
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/09/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Ethnicity-determined T cell responses and GARP/TGFbeta1 signaling in prostate cancer - Project Summary Prostate cancer (PCa) incidence and mortality rates are the highest in African American (AA) men compared to any other racial/ethnic population. These differences persist even after accounting for socioeconomic factors, suggesting genetics and unknown biological factors may contribute to PCa health disparities. However, common genetic alterations, such as TMPRRSS2-ERG gene fusions and PTEN loss, were found to occur much less frequently in AA PCa than in European American (EA) PCa. Instead, prominent differences in tumor immunobiology between AA vs. EA men were reported in several studies, including a clinical trial with a cancer vaccine, Sipuleucel-T, which AA men had a median nine-month of overall survival advantage over EA men. To mechanistically dissect the immunological and/biological factors that determine tumor cell sensitivity and resistance to immunotherapy of different races, we have developed primary cultures of AA and EA PCa patient-derived tumor organoids, normal organoids, carcinoma associated fibroblasts (CAFs) and benign- associated fibroblasts (BAFs) from many patients and cryopreserved their peripheral blood lymphocytes (PBLs) from the same patient over past years. Our preliminary data show that AA CAFs secrete increased levels of active TGF- in the culture medium than EA CAFs. In addition, we are the first to show that Glycoprotein A repetitions predominant (GARP), the docking receptor for the release of active TGF-β, is over expressed in the adjacent stroma of AA PCa compared to adjacent stroma of EA PCa and AA PCa tissues. Interestingly, the adjacent stroma of AA PCa has increased infiltration of cytotoxic CD8+T cells compared to the adjacent stroma of EA PCa and to the distant stroma of AA PCa, suggesting that immune response is higher in AA stroma but may not be effective due to the increased TGF-β1 and GARP. Our preliminary data of co-culture studies with CAFs and T cells lends further support to the scenario as we observed increased TGF-β1 and reduced IFN-  in these co-cultures. These results suggest that although AA PCa patients may be more responsive to immunotherapies, GARP/TGFβ signaling represents a vulnerable point in AA PCa and may be used as a target for developing more effective immunotherapies. Therefore, we hypothesize that the interaction between tumor and stroma in AA and EA PCa differentially affect the tumor reactivity of T cells and that GARP/TGF-β signaling contribute to the differences in the T cell tumor reactivity among patients. To test the hypothesis, first we will determine whether T cells from AA and EA PCa patients display differences in tumor reactivity in co-cultures with autologous tumor organoids and/or CAFs. Second, our preliminary data have shown that Dabigatran etexilate, an anticoagulant drug for preventing stroke in people with atrial fibrillation, effectively blocks GARP/TGF-1 signaling and that its combination with anti-CTLA4 results in a durable regression of Myc-CaP xenograft tumors. We therefore will determine whether Dabigatran can enhance the anti-PD1/anti-CTLA4’s anti-PCa efficacy in the HiMyc and TRAMP transgenic PCa mouse models. Third, to further enhance the clinical relevance of our study, we will utilize available formalin fixed paraffin embedded tissue blocks from 141 AA and 141 EA matched PCa cases by age and Gleason score and determine the relationship between GARP/TGF-β signaling and various infiltrating immune cells in tumor and stroma of AA and EA PCa. Impact: This proposal capitalizes on the development of unique organoids and cell resources, which allow dissecting factors and mechanisms (i.e. GARP/GARP/TGF-β) signaling leading to immune differences between AA and EA PCa. In addition, a novel strategy for enhancing immune checkpoint therapies in PCa in general and AA PCa in particular may be developed by repurposing Dabigatran etexilate through targeting GARP/TGF-β signaling that is highly activated in the tumor microenviron


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: 2026 ( Subtotal = $323,224 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	5	12/8/2025	NON-COMPETING CONTINUATION	$323,224
														Subtotal = $323,224

Issue Date FY: 2025 ( Subtotal = $359,138 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	4	6/13/2025	NON-COMPETING CONTINUATION	$35,914
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	4	11/14/2024	NON-COMPETING CONTINUATION	$323,224
														Subtotal = $359,138

Issue Date FY: 2024 ( Subtotal = $341,181 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$17,957
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	3	11/9/2023	NON-COMPETING CONTINUATION	$323,224
														Subtotal = $341,181

Issue Date FY: 2023 ( Subtotal = $351,711 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	2	3/20/2023	NON-COMPETING CONTINUATION	$28,711
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	2	11/17/2022	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $351,711

Issue Date FY: 2022 ( Subtotal = $370,628 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	1	12/9/2021	NEW	$370,628
														Subtotal = $370,628

Grand Total All Awards = $1,745,882

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Ethnicity-determined T cell responses and GARP/TGFbeta1 signaling in prostate cancer

Award Number: R01CA260351

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/09/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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