T Cell-Specific BRCA1 Function in Antitumor Immunity and Immunotherapy

摘要 具有BRCA 1生殖系突变的女性患乳腺癌的风险约为80%。所有 生殖系BRCA 1突变携带者中的体细胞具有相同的BRCA 1基因突变拷贝，但BRCA 1 研究几乎完全集中在BRCA 1在修复乳房双链DNA断裂中的作用上 上皮这是由于当前BRCA 1范式的主要原则-增加的遗传不稳定性， 乳腺上皮仅驱动BRCA 1突变相关乳腺癌的发展。此外，目前 预防性降低风险的手术旨在减少BRCA 1乳腺上皮细胞的肿瘤发生 变异携带者相比之下，几乎没有人知道BRCA 1杂合性在细胞中是否超过 乳腺上皮也可能参与BRCA 1相关的肿瘤发生。 免疫系统检测和消除肿瘤细胞的能力可对抗肿瘤形成。很显然， 受损的抗肿瘤免疫使免疫逃避和肿瘤生长成为可能。我们最近发现， BRCA 1生殖系突变与年龄匹配的野生型供体相比，循环CD 8 + T细胞的丰度较低。 型BRCA 1基因。为了支持这一临床发现，在CD 8 + T细胞中特异性地杂合敲除Brca 1， 足以减弱抗肿瘤免疫力。根据我们的初步数据，我们假设T细胞- BRCA 1在增强抗肿瘤免疫中的内在功能有助于整体肿瘤 BRCA 1的抑制活性。我们进一步提出，在BRCA 1突变携带者中， 乳腺上皮细胞的不稳定性和CD 8 + T细胞中减弱的抗肿瘤免疫力共同作用， 癌症发病率为了验证这一新的假设，我们将联合收割机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通过以下三个具体目标： (1)探讨T细胞内源性BRCA 1对抗肿瘤免疫和免疫治疗的影响。 BRCA 1在抗肿瘤免疫中作用的分子基础;（3）检测BRCA 1突变相关的T细胞 人体样本的缺陷。 我们提出的工作代表了一个新的方向，阐明了以前不受重视的肿瘤抑制， BRCA 1在免疫细胞中的作用有待验证的概念显然背离了普遍的模式 关于BRCA 1相关的癌症病因学，重点是乳腺上皮和DNA修复。从 从翻译的角度来看，我们提出的研究重点是免疫细胞中的BRCA 1，这可能会为发展提供信息。 为BRCA 1生殖系突变的女性提供新的免疫增强策略。因此，这一行的工作， 对降低乳腺癌风险具有深远和持续影响的潜力。

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.