Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA.
Department of Chinese Medicine Information Science, Beijing University of Chinese Medicine, Beijing 102488, China.
Sci Adv. 2020 Nov 27;6(48). doi: 10.1126/sciadv.abc3243. Print 2020 Nov.
Major histocompatibility complex (MHC)-unrestricted cytotoxic lymphocytes (CLs) such as natural killer (NK) cells can detect and destroy tumor and virus-infected cells resistant to T cell-mediated killing. Here, we performed genome-wide genetic screens to identify tumor-intrinsic genes regulating killing by MHC-unrestricted CLs. A group of genes identified in our screens encode enzymes for the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, which is not involved in tumor response to T cellmediated cytotoxicity. Another gene identified in the screens was , which encodes a subunit of the PBAF form of the SWI/SNF chromatin-remodeling complex. mutations in tumor cells cause resistance to MHC-unrestricted killing, in contrast to their sensitizing effects on T cellmediated killing. PBRM1 and the GPI biosynthetic pathway regulate the ligands of NK cell receptors in tumor cells and promote cytolytic granule secretion in CLs. The regulators identified in this work represent potential targets for cancer immunotherapy.
主要组织相容性复合体（MHC）非限制细胞毒性淋巴细胞（CLs），如自然杀伤（NK）细胞，能够检测和破坏对 T 细胞介导的杀伤有抗性的肿瘤和病毒感染细胞。在这里，我们进行了全基因组遗传筛选，以鉴定调节 MHC 非限制 CLs 杀伤的肿瘤内在基因。我们的筛选中鉴定的一组基因编码糖基磷脂酰肌醇（GPI）锚的生物合成酶，该酶不参与肿瘤对 T 细胞介导的细胞毒性的反应。筛选中鉴定的另一个基因是 ，它编码 SWI/SNF 染色质重塑复合物 PBAF 形式的一个亚基。肿瘤细胞中的 突变导致对 MHC 非限制杀伤的抗性，与它们对 T 细胞介导的杀伤的致敏作用相反。PBRM1 和 GPI 生物合成途径调节肿瘤细胞中 NK 细胞受体的配体，并促进 CLs 中的细胞溶解颗粒分泌。本工作中鉴定的调节剂代表癌症免疫治疗的潜在靶点。
