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TOX-driven CD8 T cell differentiation and dysfunction in tumors

Award Number: R01CA269733
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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TOX-driven CD8 T cell differentiation and dysfunction in tumors - PROJECT SUMMARY CD8 T cells specific for cancer cells are found within human tumors, but despite their presence, tumors progress, suggesting that T cells become unresponsive. To design predictably effective immunotherapies, we must elucidate the mechanisms controlling tumor-specific T cell dysfunction. We previously demonstrated that T cells in tumors enter an epigenetically encoded dysfunction state that becomes resistant to therapeutic reprogramming and found that TOX, a DNA-binding protein, is a key regulator enforcing the dysfunctional state. The factors that drive TOX expression, and how TOX precisely establishes the dysfunction program remain largely unknown. TCR signal strength impacts T cell differentiation, and while we know that antigen chronicity is a key driver of TOX-driven T cell dysfunction, we do not know how signal strength of chronic tumor antigen impacts TOX-driven dysfunction and amenability to immunotherapeutic reprogramming. In this application, we will determine how signal strength regulates TOX and TOX-driven dysfunction programs in mouse and human tumors, ask how TOX induces and maintains dysfunction, and target TOX and its downstream mediators to uncover the mechanisms underlying dysfunction imprinting. To achieve these goals, we will utilize clinically relevant genetic cancer mouse models and track T cells longitudinally within progressing tumors while encountering tumor antigens with varying signal strength. We will employ transcriptomic and epigenomic methods and innovative protein degradation strategies to determine what controls TOX, how TOX induces and/or maintains dysfunction, and how TOX downstream mediators regulate the epigenetic programs associated with plasticity and dysfunction imprinting. We will leverage human neoantigen- specific tumor-infiltrating T cell resources to understand how TCR signal strength determines TOX- dependent molecular signatures and functional states of T cells in human tumors. Importantly, we will test and design strategies to target TOX and TOX downstream mediators to improve cancer immunotherapy.


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 = $542,566 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	4	12/30/2025	NON-COMPETING CONTINUATION	$542,566
														Subtotal = $542,566

Issue Date FY: 2025 ( Subtotal = $602,850 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	3	5/30/2025	NON-COMPETING CONTINUATION	$60,284
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	3	12/4/2024	NON-COMPETING CONTINUATION	$542,566
														Subtotal = $602,850

Issue Date FY: 2024 ( Subtotal = $577,535 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	2	12/12/2023	NON-COMPETING CONTINUATION	$547,139
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$30,396
														Subtotal = $577,535

Issue Date FY: 2023 ( Subtotal = $617,017 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	12/21/2022	NEW	$617,017
														Subtotal = $617,017

Grand Total All Awards = $2,339,968

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TOX-driven CD8 T cell differentiation and dysfunction in tumors

Award Number: R01CA269733

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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