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

• 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
• 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

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 携带BRCA1胚系突变的女性一生中患乳腺癌的风险约为80%。全 生殖系BRCA1突变携带者的体细胞具有相同的BRCA1基因突变拷贝，但BRCA1 研究几乎完全集中在BRCA1的S在乳腺双链DNA断裂修复中的作用 上皮组织。这是由于当前BRCA1范式的主要原则-增加了基因不稳定性 乳腺上皮细胞单独驱动BRCA1突变相关乳腺癌的发生。此外，目前 预防性降低风险手术旨在抑制BRCA1乳腺上皮细胞的肿瘤形成 突变携带者。相比之下，对于BRCA1杂合性是否存在于细胞外，几乎一无所知。 乳腺上皮也可能参与BRCA1相关肿瘤的发生。 免疫系统检测和清除肿瘤细胞的能力可以对抗肿瘤的形成。显然， 抗肿瘤免疫功能受损导致免疫逃逸和肿瘤生长。我们最近发现，患有癌症的女性 BRCA1胚系突变的循环CD8+T细胞比年龄匹配的野生型供者少。 BRCA1基因分型。为了支持这一临床发现，在CD8+T细胞中特异性地杂合敲除BRCA1 足以减弱小鼠的抗肿瘤免疫。根据初步数据，我们假设T细胞- BRCA1在增强抗肿瘤免疫中的内在功能在整个肿瘤中的作用 BRCA1的抑制活性。我们进一步提出，在BRCA1突变携带者中，基因组增加 乳腺上皮的不稳定和CD8+T细胞中抗肿瘤免疫的减弱共同作用提高 癌症发病率。为了验证这一新的假设，我们将结合我们现有团队的工具和专业知识 在癌症生物学、肿瘤免疫学和转录调控方面，通过以下三个特定目标： (1)识别T细胞固有的BRCA1在抗肿瘤免疫和免疫治疗中的作用；(2)阐明BRCA1在抗肿瘤免疫中的作用 BRCA1‘S在抗肿瘤免疫中作用的分子基础；(3)检测BRCA1突变相关T细胞 人体样本中的缺陷。 我们提出的工作代表了阐明一种以前未被认识的肿瘤抑制作用的新方向 BRCA1在免疫细胞中的作用。需要验证的概念显然偏离了流行的范例 关于BRCA1相关的癌症病因学，其重点是乳腺上皮和DNA修复。从一个 从翻译的角度来看，我们建议的专注于免疫细胞中BRCA1的研究可能会为发育提供信息 为具有BRCA1种系突变的女性提供新的免疫增强策略。因此，这项工作具有 可能对降低乳腺癌风险产生深远和持续的影响。