# Epigenetic Reprogramming of T cell Exhaustion To Enhance Tumor Immunotherapy

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $390,077

## Abstract

SUMMARY: CD8 T cells are a critical part of the immune system that protect against intracellular pathogens and
cancer. This protection is achieved by the T cell’s ability to target and kill tumor cells or cells infected with a
pathogen. Upon clearance of the diseased cells, pathogen-specific CD8 T cells can persist for the life of the host,
ready to rapidly recall their killing functions if the source of the antigen returns. This poised state of memory T
cells is the basis for long-lived immunity. However, if the source of the disease is not initially cleared, as occurs
during chronic infections or cancers, the killing functions of pathogen-specific CD8 T cells are progressively
reduced, commonly referred to as T cell exhaustion. This reduction in T cell mediated killing limits the ability of
the immune system to control tumor progression. Recent breakthroughs in our understanding of T cell
exhaustion have revealed that the non-functional state can be temporarily reversed by therapies that block
receptor signaling (PD-1) on the T cell, enabling T cell mediated tumor control. In light of the tremendous
therapeutic effect PD-1 blockade has on controlling tumor progression, the FDA has recently approved it for
clinical use. While PD-1 blockade therapy clearly controls tumor progression, the temporarily reactivated CD8
T cells retain a memory of the non-functional state. Therefore, a current challenge for the field is to identify the
cell-intrinsic properties that maintain T cell exhaustion after PD-1 treatment. We have recently demonstrated that
epigenetic modifications (modifications to the genome that are maintained during cell division) acquired during
prolonged antigen exposure reinforces T cell exhaustion by maintaining exhaustion-specific gene expression
programs. We hypothesize that these epigenetic programs are a major barrier for therapeutic strategies that
aim to reprogram exhausted tumor-specific T cells. Therefore, the aims of our proposal are 1) To identify de
novo DNA methylation programs that reinforce commitment of T cell exhaustion in mouse and human
tumor-specific CD8 T cells. 2) To erase de novo DNA methylation programs that constrain rejuvenation
of exhausted CD8 T cells during immune checkpoint blockade (ICB). 3) To determine if CAR T cell
exhaustion is regulated by de novo DNA methylation. The research proposed here will broadly identify gene
expression programs in antigen-specific CD8 T cells that inhibit anti-tumor functions, and will provide new insight
into the cell-intrinsic mechanisms for maintenance of exhaustion programs. These studies will provide a
foundation for developing methods to reprogram exhausted CD8 T cells to sustain effector potential during and
after immune checkpoint blockade and CAR T-cell therapies.

## Key facts

- **NIH application ID:** 10799545
- **Project number:** 5R01CA237311-05
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Benjamin Alan Youngblood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,077
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799545

## Citation

> US National Institutes of Health, RePORTER application 10799545, Epigenetic Reprogramming of T cell Exhaustion To Enhance Tumor Immunotherapy (5R01CA237311-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10799545. Licensed CC0.

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