# Epigenetic Regulation of Immune Evasion in Bladder Cancer

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2021 · —

## Abstract

Bladder cancer is the fourth most common cancer in men and a significant burden for Veterans and the VHA
due to the high frequency of recurrence and progression linked to smoking and exposure to deployment-related
carcinogens. Less than 45% of patients with Stage IV bladder cancer survive more than a year in the VA
suggesting the aggressive nature of metastatic urothelial tumors identified among Veterans. The primary cause
of death from bladder cancer is resistance to therapy as these invasive carcinomas acquire cellular plasticity and
stem cell-like properties from long-term changes in epigenetic regulators. In our first VA Merit Award, we first
genomically validated a carcinogen-induced bladder cancer model that replicated smoking induced bladder
cancer and shared the somatic alterations found in locally advanced bladder cancers. To re-establish an
epigenetic balance, we then identified a significant decrease in carcinogen-induced bladder cancers in mice
treated with an enzymatic EZH2-inhibitor. While bladder tumors decreased in size after treatment, we found a
significant increase in the CD3+ T cell immune infiltrate associated with tumor regression. These results were
rapidly translated into an NCI-sponsored clinical trial for patients with metastatic bladder cancer (ETCTN#10183).
In this Phase I/II clinical trial, we are currently treating patients with an EZH2-inhibitor (tazemetostat) and a PD1
inhibitor (pembrolizumab). The PI of this application is the co-PI of the trial and despite clinical response there
remains much to be investigated about the immunotherapy in bladder cancer and how a histone modifying
complex (polycomb repressor complex 2, and EZH2) is involved in immune evasion. The long-term goal of our
research is to investigate the molecular and epigenetic pathways associated with immune evasion of bladder
cancer. By understanding these mechanisms, we may develop rational and novel therapeutics for Veterans with
bladder cancer that combine precision targets and immunotherapy. Given this preliminary data, our central
hypothesis is that EZH2 drives immune evasion by three distinct mechanisms that will be focus of this VA Merit
proposal. In Aim 1 we will determine how EZH2 regulates antigen presentation by MHCI and MHCII to evade
immune detection. In Aim 2, we evaluate how inhibition of EZH2 leads to recruitment of T cells to tumor
microenvironment and in Aim 3 will focus on the action of EZH2 in Tregulatory cells that suppress an immune
response. Through a multi-disciplinary collaboration we have demonstrated feasibility with our approach with
rapid translation from bench to bedside. Successful completion of the studies described in this proposal will
provide an innovative approach to both investigate the mechanisms involved in the evasion of the immune
system of bladder cancer and potentially identify a novel therapeutic approach to treat bladder cancer.

## Key facts

- **NIH application ID:** 10122077
- **Project number:** 2I01BX003692-05
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Joshua James Meeks
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2016-10-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122077

## Citation

> US National Institutes of Health, RePORTER application 10122077, Epigenetic Regulation of Immune Evasion in Bladder Cancer (2I01BX003692-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10122077. Licensed CC0.

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