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Exploring host GSK3β-53BP1 axis in immune control of solid tumor progression

Award Number: R01CA299654
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Exploring host GSK3β-53BP1 axis in immune control of solid tumor progression - Summary Head and neck squamous cell carcinoma (HNSCC) is a major global health challenge, with a high rate of recurrence and metastasis leading to a median survival of only 10-12 months for patients with advanced disease. While immune checkpoint blockade (ICB) has revolutionized treatment, its effectiveness remains limited, with a response rate of only 11-18% at six months. This proposal seeks to address the critical issue of T cell exhaustion (TEX), which hampers the efficacy of immunotherapies like ICB and adoptive cell transfer (ACT). Our preliminary data indicate that TEX is associated with the accumulation of DNA double-strand breaks (DSBs), resulted from the inhibition of the 53BP1-dependent DNA repair activity by glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation. We have developed a knock-in mouse model that expresses a mutant 53BP1 which prevents GSK3β-mediated phosphorylation and inhibition. Using our model, we discovered that blocking this GSK3β- 53BP1 interaction in mouse models significantly enhanced T cell survival following ironing radiation-induced DSBs, infiltration into tumors, and immunotherapy responses in pre-clinical models HNSCC. We hypothesize that inhibition of the GSK3B-53BP1 axis in T cells will enhance DNA repair, promote survival from DNA damage, limit TEX, and increase immune effector function in HNSCC. Aim 1 focuses on understanding how GSK3β inhibits 53BP1 in DNA repair and T cell survival following radiation, hypothesizing that this interaction is crucial for controlling TEX. Aim 2 will investigate the effects of disrupting the GSK3β-53BP1 axis on tumor-infiltrating lymphocyte (TIL) function and the response to ICB alone, or in combination with radiation. Aim 3 tests the therapeutic potential of using 53BP1 mutant T cells in ACT for HNSCC. This study will be the first to explore the GSK3β-53BP1 axis in cancer immunity, aiming to enhance DNA repair, reduce TEX, and improve the efficacy of immunotherapies for HNSCC and other solid tumors.


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 = $628,980 )
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Treatment Research	000	1	4/21/2026	NEW	$628,980
														Subtotal = $628,980

Grand Total All Awards = $628,980

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Exploring host GSK3β-53BP1 axis in immune control of solid tumor progression

Award Number: R01CA299654

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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