# Understanding how T cell intrinsic androgen receptor activity influences cell differentiation and dysfunction

> **NIH NIH R37** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $544,635

## Abstract

PROJECT SUMMARY
Androgens are well known to be immunosuppressive, yet cancer immunotherapy is used without consideration
of local androgen concentrations or the sex of the patient. We present evidence that targeting the androgen
receptor is necessary for effective T cell-specific immunotherapy in mouse models of prostate cancer and
sarcoma and in a human clinical trial of metastatic prostate cancer. In patient biopsies, we observed a striking
correlation between low androgen receptor activity in CD8 T cells and response to PD-1 targeted
immunotherapy. We validated our observations in a novel mouse model of castration resistant prostate cancer
and demonstrated a requirement for androgen receptor inhibition to permit effective PD-L1 immunotherapy.
Moreover, tumor regression required CD8 T cells suggesting T cell intrinsic AR activity could regulate response
to immunotherapy. Extending these studies, we isolated activated CD8 T cells and observed a strong association
of androgen receptor with chromatin modifiers. Performing in silico experiments revealed canonical androgen
response elements in open chromatin regions of the Ifng and Gzmb loci. We observed binding of the androgen
receptor within these regions and importantly, the ability to inhibit this interaction with a small molecule inhibitor.
Inhibiting this interaction increased the functional capacity of dysfunctional CD8 T cells; a functional state further
amplified by PD-L1 blockade. Taken together, these observations suggest that androgen receptor signaling
could enforce the dysfunctional chromatin state of T cells limiting reinvigoration by checkpoint blockade. To the
best of our knowledge this is the first experimental model to establish a direct role for androgen receptor
activity on regulating responsiveness to immunotherapy.
The goal of this proposal is to understand the mechanism(s) by which androgen receptor activity in CD8 T cells
limits the effectiveness of cancer immunotherapy. We hypothesize that androgen receptor activity in CD8 T
cells limits functional re-invigoration to immune checkpoint blockade by transcriptional and epigenetic
repression of effector genes. We will test this hypothesis in the following Aims. 1) Evaluate whether AR activity
represses T cell effector genes by direct DNA binding; 2) Determine whether AR signaling enforces a repressive
chromatin state in dysfunctional CD8 T cells; and 3) Determine whether loss of T cell intrinsic AR is sufficient to
restore responsiveness to checkpoint blockade.
Together, these studies provide a framework for understanding hormone mediated resistance to cancer
immunotherapy. Importantly, we will gain a critical understanding of how androgen could limit effective
immunotherapy in prostate cancer patients and anticipate that our observations will be applicable beyond this
disease to improve immunotherapy outcomes in cancers where androgens are present.

## Key facts

- **NIH application ID:** 10445347
- **Project number:** 5R37CA263592-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Amy E Moran
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $544,635
- **Award type:** 5
- **Project period:** 2021-07-06 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445347

## Citation

> US National Institutes of Health, RePORTER application 10445347, Understanding how T cell intrinsic androgen receptor activity influences cell differentiation and dysfunction (5R37CA263592-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10445347. Licensed CC0.

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