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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $370,628

## Abstract

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 My...

## Key facts

- **NIH application ID:** 10358338
- **Project number:** 1R01CA260351-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Anshu Agrawal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $370,628
- **Award type:** 1
- **Project period:** 2021-12-09 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358338

## Citation

> US National Institutes of Health, RePORTER application 10358338, Ethnicity-determined T cell responses and GARP/TGFbeta1 signaling in prostate cancer (1R01CA260351-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10358338. Licensed CC0.

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