# Dissecting the enhancer logic governing immune cell fate decisions

> **NIH NIH DP2** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $1,512,000

## Abstract

Project Summary
CD8 T cells are a critical component of an effective anti-tumor response. Therefore, a major goal in cancer
immunology, and more broadly in immunobiology, has been to understand how specific disease contexts
govern T cell fate and function. A growing and largely descriptive atlas of chromatin accessibility has begun
providing rich insight into the epigenetic landscape of CD8 T cells, yet it remains a challenge to understand
cause-and-effect relationships from such data. Furthermore, T cell fate specification, like many cellular
differentiation processes, develops with a continuum of phenotypic and functional intermediate states. This
prompts the question, which epigenetic mechanisms are causal in driving state transitions within CD8 T cells?
What are the earliest signaling pathways that drive commitment to particular T cell phenotype? How does
tissue context shape anti-tumor T cell immunity? Our proposal addresses these questions by leveraging loss-
of-function (LOF) and gain-of-function (GOF) approaches for enhancer editing to identify how, when and where
CD8 T cell fate commitment happens in vivo. As an initial application, we will use this framework to understand
the context-specific epigenetic mechanisms governing exhausted CD8 T cell differentiation in the tumor
microenvironment. We focus in particular on comparing progenitor exhausted T cells in melanoma vs.
hepatocellular carcinoma since these two diseases have markedly different tissue-specific signaling, have
differential responsivity to immune checkpoint blockade, and most importantly, induce both shared and tumor-
specific patterns of epigenetic changes. Although this project will yield fundamental insights into T cell
regulation, we also aim to extend epigenetic reprogramming to preclinical models of adoptive T cell therapy
with potential therapeutic application. The novel integration of technologies to achieve these goals promises to
be useful for diverse disease contexts where CD8 T cells play a role, in cancer and beyond.

## Key facts

- **NIH application ID:** 10472872
- **Project number:** 1DP2AI176139-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Debattama Rai Sen
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,512,000
- **Award type:** 1
- **Project period:** 2022-09-09 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472872

## Citation

> US National Institutes of Health, RePORTER application 10472872, Dissecting the enhancer logic governing immune cell fate decisions (1DP2AI176139-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10472872. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*