BRCA1 deficiency in mature CD8⁺ T lymphocytes impairs antitumor immunity

Abstract

Women with <i>BRCA1</i> 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 <i>BRCA1</i> deficiency in non-breast somatic cells also contribute to tumorigenesis. Here, we report that mouse <i>Brca1</i> 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 <i>Brca1</i> KO on antitumor adaptive immunity. T cell-specific <i>Brca1</i> 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 <i>BRCA1</i> mutation-carrying women display lower abundance of circulating CD8⁺ lymphocytes than the age-matched control group. Thus, our findings support the notion that <i>BRCA1</i> deficiency in adaptive immunity could contribute to <i>BRCA1</i>-related tumorigenesis. We also suggest that prophylactic boosting of adaptive immunity may reduce cancer incidence among at-risk women.