BRCA1 deficiency in mature CD8<sup>+</sup> T lymphocytes impairs antitumor immunity
Bogang Wu, Leilei Qi, Huai-Chin Chiang, Haihui Pan, Xiaowen Zhang, Alexandra Z. Greenbaum, Elizabeth Stark, Li‐Ju Wang, Yidong Chen, Bassem R. Haddad, Dionyssia Clagett, Claudine Isaacs, Richard Elledge, Anélia Horvath, Yanfen Hu, Rong Li
Abstract
Women with BRCA1 germline mutations have approximately an 80% lifetime chance of developing breast cancer. While the tumor suppressor function of BRCA1 in breast epithelium has been studied extensively, it is not clear whether BRCA1 deficiency in non-breast somatic cells also contribute to tumorigenesis. Here, we report that mouse Brca1 knockout (KO) in mature T lymphocytes compromises host antitumor immune response to transplanted syngeneic mouse mammary tumors. T cell adoptive transfer further corroborates CD8 + T cell-intrinsic impact of Brca1 KO on antitumor adaptive immunity. T cell-specific Brca1 KO mice exhibit fewer total CD8 + , more exhausted, reduced cytotoxic, and reduced memory tumor-infiltrating T cell populations. Consistent with the preclinical data, cancer-free BRCA1 mutation-carrying women display lower abundance of circulating CD8 + lymphocytes than the age-matched control group. Thus, our findings support the notion that BRCA1 deficiency in adaptive immunity could contribute to BRCA1 -related tumorigenesis. We also suggest that prophylactic boosting of adaptive immunity may reduce cancer incidence among at-risk women.