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T Cell-Specific BRCA1 Function in Antitumor Immunity and Immunotherapy

T 细胞特异性 BRCA1 在抗肿瘤免疫和免疫治疗中的功能

基本信息

批准号：
10716957
负责人：
YANFEN HU
金额：
$ 61.46万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716957
关键词：
Affect Age Attenuated BRCA1 Mutation BRCA1 gene Breast Epithelial Cells CD8-Positive T-Lymphocytes Cancer Biology Cancer Etiology Cells Cellular biology Clinical Complement Coupled DNA Double Strand Break DNA Repair Data Defect Development Dimensions Double Strand Break Repair Epithelium Foundations Genetic Genomic Instability Germ-Line Mutation Heterozygote Human Immune Immune Evasion Immune system Immunotherapy Impairment Incidence Knock-out Knowledge Label Laboratory Finding Malignant Neoplasms Mass Spectrum Analysis Mature T-Lymphocyte Molecular Mus Neoplasms Oncogenes Operative Surgical Procedures Positioning Attribute Research Risk Risk Reduction Role Sampling Somatic Cell T-Lymphocyte Technology Testing Time Transcriptional Regulation Tumor Immunity Tumor Suppressor Proteins Woman Work breast tumorigenesis cancer immunotherapy cancer prevention cancer risk cohort driving force epithelial repair experimental study genomic tools lifetime risk malignant breast neoplasm mammary epithelium mouse genetics multidisciplinary mutant mutant mouse model mutation carrier mutational status neoplasm immunotherapy neoplastic cell novel preclinical study prophylactic repaired response tool translational impact tumor tumor immunology tumorigenesis virtual

项目摘要

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.

摘要