# Project 3: Genetic and epigenetic basis of resistance to RT and ICB

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $534,183

## Abstract

SUMMARY
Resistance to Immune Checkpoint Blockade (ICB) and failure to develop durable immunity after partial
responses may occur through intrinsic or acquired mechanisms. Mechanistic details and clinical correlates on
how cancer escapes ICB are lacking. In previous work, we discovered that resistance to combination ICB
therapy consisting of radiation (RT) and anti-CTLA4 can occur with upregulation of PDL1. This is associated
with increased expression of interferon-stimulated genes (ISGs). Our preliminary data reveal a key role for
tumor-intrinsic resistance mechanisms driven by prolonged interferon (IFN) signaling and related to tumor
burden. Moreover, recent clinical results define a link between tumor burden and efficacy of ICB revealed by
changes in exhausted T cells (TEX). We have found critical transcriptional and epigenetic events in both tumor
cells and responding TEX that may reveal PDL1-independent mechanisms of resistance that are driven by
prolonged IFN signaling and tumor burden. To complement parallel clinical trials that test the combination of
RT + αCTLA4 + αPD1 in patients with advanced cancer, this project seeks to investigate PDL1-independent
resistance mechanisms by examining both tumor cells and T cells. We will test the hypothesis that tumor
burden and prolonged IFN signaling lead to reciprocal genomic/epigenomic changes in both cell types that limit
the efficacy of RT + αCTLA4 + αPDL1/PD1, and that the reversibility of these genomic/epigenomic changes
impacts the efficacy and durability of responses. By integrating pre-clinical and clinical efforts, our goal is to
understand how IFN, a major signal in the tumor microenvironment, can paradoxically drive additional but
targetable immune checkpoint pathways to control T cell exhaustion and resistance to combination therapy. In
so doing, we will inform the design of the next generation of clinical trials by focusing on underlying
determinants of durable response.

## Key facts

- **NIH application ID:** 10360425
- **Project number:** 5P01CA210944-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** E. John Wherry
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $534,183
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360425

## Citation

> US National Institutes of Health, RePORTER application 10360425, Project 3: Genetic and epigenetic basis of resistance to RT and ICB (5P01CA210944-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10360425. Licensed CC0.

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