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T Cell-Specific BRCA1 Function in Antitumor Immunity and Immunotherapy

Award Number: R01CA282303
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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T Cell-Specific BRCA1 Function in Antitumor Immunity and Immunotherapy - ABSTRACT Women with germline mutations of BRCA1 have about an 80% lifetime risk of developing breast cancer. All somatic cells in a germline BRCA1 mutation carrier harbor the same mutant copy of the BRCA1 gene, yet BRCA1 research is almost exclusively focused on BRCA1’s role in repair of double-strand DNA breaks in the breast epithelium. This is due to the cardinal tenet of the current BRCA1 paradigm — increased genetic instability of the breast epithelium solely drives development of BRCA1 mutation-related breast cancer. In addition, current prophylactic risk-reducing surgeries are aimed at curtailing tumorigenesis of breast epithelial cells of BRCA1 mutation carriers. In contrast, virtually nothing is known about whether BRCA1 heterozygosity in cells beyond the breast epithelium could also contribute to BRCA1-related tumorigenesis. Neoplasia is antagonized by the ability of the immune system to detect and eliminate neoplastic cells. Clearly, impaired antitumor immunity enables immune evasion and tumor outgrowth. We recently found that women with BRCA1 germline mutations have less abundant circulating CD8+ T cells versus age-matched donors with wild- type BRCA1 genes. In support of this clinical finding, heterozygous knockout of Brca1 specifically in CD8+ T cells of mice is sufficient to attenuate antitumor immunity. Based on our preliminary data, we hypothesize that T cell- intrinsic function of BRCA1 in enhancing antitumor immunity contributes to the overall tumor suppressor activity of BRCA1. We further propose that in BRCA1 mutation carriers, increased genomic instability in the breast epithelium and attenuated antitumor immunity in CD8+ T cells act together to elevate cancer incidence. To validate this novel hypothesis, we will combine our established team’s tools and expertise in cancer biology, tumor immunology, and transcriptional regulation through the following three Specific Aims: (1) Discern the impact of T cell-intrinsic BRCA1 on antitumor immunity and immunotherapy, (2) Elucidate the molecular basis for BRCA1’s function in antitumor immunity, and (3) Examine BRCA1 mutation-related T cell deficiency in human samples. Our proposed work represents a new direction in elucidating a previously unappreciated tumor-suppressing function of BRCA1 in immune cells. The concept to be validated clearly departs from the prevailing paradigm regarding BRCA1-related cancer etiology, which is focused on the breast epithelium and DNA repair. From a translational perspective, our proposed study focusing on BRCA1 in immune cells will likely inform development of novel immune-boosting strategies for women with BRCA1 germline mutations. Thus, this line of work has potential for far-reaching and sustained impact on breast cancer cancer risk reduction.


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: 2025 ( Subtotal = $614,606 )
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	3	6/13/2025	NON-COMPETING CONTINUATION	$614,606
														Subtotal = $614,606

Issue Date FY: 2024 ( Subtotal = $583,876 )
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	2	6/25/2024	NON-COMPETING CONTINUATION	$583,876
														Subtotal = $583,876

Issue Date FY: 2023 ( Subtotal = $614,606 )
2023	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	1	7/3/2023	NEW	$614,606
														Subtotal = $614,606

Grand Total All Awards = $1,813,088

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T Cell-Specific BRCA1 Function in Antitumor Immunity and Immunotherapy

Award Number: R01CA282303

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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