# Treg functional changes: a novel immune regulatory effect underlying the benefit of statin drug use on lethal prostate cancer

> **NIH NIH R00** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $249,000

## Abstract

PROJECT SUMMARY
Prior research has demonstrated a consistently strong inverse association between statin drug use and risk of
developing lethal prostate cancer, and a stronger protective effect with a longer duration of use. Further, in
men with clinically localized prostate cancer, statins are associated with a reduced risk of progression to
metastasis and dying from prostate cancer. For statins to have clinical utility as chemopreventive and
therapeutic (adjuvant) agents, additional characterization of the mechanisms through which statins interact with
the tumor microenvironment is needed. Yes-associated protein (YAP) is a transcriptional regulator highly
expressed in regulatory T lymphocytes (Tregs). Statin drugs have been shown to inhibit YAP nuclear
translocation (via YAP phosphorylation) required for Foxp3-meditated Treg immunosuppressive function. Thus,
we propose to investigate the association between statin drugs and YAP-mediated Treg dysfunction, a novel
immune-modulatory mechanism through which statins may impede development and progression of lethal
prostate cancer in the following specific aims. For Aim 1 (K99 phase) we will create a new tissue microarray
set including statin users and nonusers at the time of prostatectomy matched on clinical pathological
characteristics. We will evaluate whether the proportion of Tregs with phosphorylated YAP in the cytoplasm of
Tregs differs between statin users and nonusers, and if the prostate immune cell profile differs among statin
users and nonusers. For Aim 2 (R00 phase), we will conduct a proof-of-principle randomized trial investigating
the effect of statins on YAP-mediated Treg dysfunction in men diagnosed with prostate cancer scheduled to
receive prostatectomy. This proof-of-principle trial will also provide a controlled environment to assess the
effect of a single type of statin and dosing schedule to overcome heterogeneity in the type of statin drugs and
dose in the observational study purposed in Aim 1. Potential biases, such as confounding by indication, will be
minimized through the use of randomization. We will leverage the tremendous expertise in the biology and
measurement of the immune cell profile present in prostate cancer tissue and our established, well
characterized prostate cancer cohorts with associated archived tissue at JHU. The translational value of this
work lies in the ability to characterize the effect of statin drugs on a novel immunemodulatory mechanism,
which may be relevant in the setting of immune-based therapy for prostate cancer. This research plan is
complemented by a training plan that builds on the applicant’s background in cancer epidemiology and
research synthesis methods and includes new training in 1) contributing an epidemiologic perspective in
multidisciplinary team science collaborations; 2) conducting tissue-biomarker validation studies; and 3) clinical
trial design and implementation. The combined research and training plans will prepare the appli...

## Key facts

- **NIH application ID:** 10554641
- **Project number:** 4R00CA246097-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Michael Thomas Marrone
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2020-03-09 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10554641

## Citation

> US National Institutes of Health, RePORTER application 10554641, Treg functional changes: a novel immune regulatory effect underlying the benefit of statin drug use on lethal prostate cancer (4R00CA246097-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10554641. Licensed CC0.

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