# FOXA1 regulates cytokine signaling and immune landscape in prostate cancer through ARID1A

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $490,082

## Abstract

Summary
Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer death
in American males. Androgen deprivation therapies and androgen receptor (AR) pathway inhibitors extend
patient lifespan, yet resistance often develops, leading to castration-resistant prostate cancer (CRPC).
Immunotherapies, such as immune checkpoint inhibitors (ICI), have shown great promise in some cancers.
However, CRPC has displayed a poor response to ICI, mainly due to tumor infiltration by immunosuppressive
cells, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM). The
accumulation of these cells inhibits CD4+/CD8+ T cell growth and activity, leading to an immunosuppressive
tumor-immune microenvironment (TIME). MDSCs and TAMs are attracted by inflammatory cytokines that are
secreted by the tumor cells under the regulation of tumor-intrinsic factors. FOXA1 is a transcription factor that
is required for normal prostate development and differentiation. However, FOXA1 is down-regulated in CRPC,
and somatic point mutations of FOXA1 were found in about 12-13% of metastatic CRPC. We have previously
shown that FOXA1 loss or mutations increase epithelial-to-mesenchymal transition (EMT), lineage plasticity,
cell motility, and PCa metastasis by inducing inflammatory cytokines such as TGFB3 and IL8. However, how
FOXA1 acts as a transcriptional repressor and whether FOXA1 regulates the immune landscape of PCa
remain unknown. In preliminary studies, we found that FOXA1 inhibits a panel of inflammatory cytokines, such
as TNFĮ, CCL2, CCL20, CXCL5, TGFB3, and IL8 that are known to recruit MDSCs and TAMs.
Mechanistically, we observed that FOXA1 protein interacts with ARID1A, a subunit of the SWI/SNF chromatin
remodeling complex that has been shown to act as a transcriptional repressor and inhibit inflammatory
cytokines in ovarian cancer. Critically, analyses of a transgenic mouse model with prostate-specific co-deletion
of Foxa1 and Pten showed a more aggressive tumor with massive macrophage infiltration than the Pten mice.
We thus hypothesize that 1) FOXA1 recruits ARID1A protein to the chromatin for epigenetic remodeling and
transcriptional repression, 2) FOXA1 loss or mutation unleashes ARID1A, leading to inflammatory cytokine
induction, an immunosuppressive TIME, and PCa progression. To test these hypotheses, in Aim 1, we will
investigate FOXA1 and ARID1A protein interaction in PCa, co-occupancy on the chromatin, and mutual
dependency for transcriptional repression of inflammatory cytokines. We will also determine how these
functions are disrupted by PCa-associated FOXA1 mutations. Aim 2 will investigate how Foxa1 depletion in
the transgenic mice affects PCa progression, Arida1a function, cytokine induction, and tumor immune
infiltration and further validate the pathway in human CRPC tissues.

## Key facts

- **NIH application ID:** 10892845
- **Project number:** 5R01CA275193-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jindan Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,082
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892845

## Citation

> US National Institutes of Health, RePORTER application 10892845, FOXA1 regulates cytokine signaling and immune landscape in prostate cancer through ARID1A (5R01CA275193-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10892845. Licensed CC0.

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