Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
Department of Anatomy & Cell Biology, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
J Immunother Cancer. 2023 Feb;11(2). doi: 10.1136/jitc-2022-005852.
Women with 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 deficiency in non-breast somatic cells also contribute to tumorigenesis. Here, we report that mouse 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 KO on antitumor adaptive immunity. T cell-specific 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 mutation-carrying women display lower abundance of circulating CD8 lymphocytes than the age-matched control group. Thus, our findings support the notion that deficiency in adaptive immunity could contribute to -related tumorigenesis. We also suggest that prophylactic boosting of adaptive immunity may reduce cancer incidence among at-risk women.
携带种系突变的女性一生中大约有 80%的机会患上乳腺癌。虽然 BRCA1 在乳腺上皮细胞中的肿瘤抑制功能已被广泛研究，但尚不清楚非乳腺体细胞中的缺陷是否也有助于肿瘤发生。在这里，我们报告说，成熟 T 淋巴细胞中的小鼠敲除（KO）会损害宿主对移植同源小鼠乳腺肿瘤的抗肿瘤免疫反应。T 细胞过继转移进一步证实了 KO 对抗肿瘤适应性免疫的 CD8 T 细胞内在影响。T 细胞特异性 KO 小鼠的总 CD8 细胞数量减少，耗竭的细胞更多，细胞毒性降低，记忆性肿瘤浸润 T 细胞减少。与临床前数据一致的是，无癌症的 BRCA1 突变携带者的循环 CD8 淋巴细胞丰度低于年龄匹配的对照组。因此，我们的研究结果支持这样一种观点，即适应性免疫缺陷可能有助于 BRCA1 相关的肿瘤发生。我们还建议预防性增强适应性免疫可能会降低高危女性的癌症发病率。
