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Dissecting the enhancer logic governing immune cell fate decisions

Award Number: DP2AI176139
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Dissecting the enhancer logic governing immune cell fate decisions - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Research Support	000	2	11/26/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $990,000 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Research Support	000	2	9/23/2025	EXTENSION WITH OR WITHOUT FUNDS	$990,000
														Subtotal = $990,000

Issue Date FY: 2022 ( Subtotal = $1,512,000 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Research Support	000	1	9/9/2022	NEW	$1,512,000
														Subtotal = $1,512,000

Grand Total All Awards = $2,502,000

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Dissecting the enhancer logic governing immune cell fate decisions

Award Number: DP2AI176139

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/09/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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