Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080.
Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080.
Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11731-E11740. doi: 10.1073/pnas.1814052115. Epub 2018 Nov 30.
Natural killer (NK) cell recognition of tumor cells is mediated through activating receptors such as CD226, with suppression of effector functions often controlled by negative regulatory transcription factors such as FOXO1. Here we show that CD226 regulation of NK cell cytotoxicity is facilitated through inactivation of FOXO1. Gene-expression analysis of NK cells isolated from syngeneic tumors grown in wild-type or CD226-deficient mice revealed dysregulated expression of FOXO1-regulated genes in the absence of CD226. In vitro cytotoxicity and stimulation assays demonstrated that CD226 is required for optimal killing of tumor target cells, with engagement of its ligand CD155 resulting in phosphorylation of FOXO1. CD226 deficiency or anti-CD226 antibody blockade impaired cytotoxicity with concomitant compromised inactivation of FOXO1. Furthermore, inhibitors of FOXO1 phosphorylation abrogated CD226-mediated signaling and effector responses. These results define a pathway by which CD226 exerts control of NK cell responses against tumors.
自然杀伤 (NK) 细胞通过激活受体（如 CD226）识别肿瘤细胞，其效应功能的抑制通常由 FOXO1 等负调控转录因子控制。在这里，我们表明 CD226 通过使 FOXO1 失活来调节 NK 细胞的细胞毒性。从在野生型或 CD226 缺陷型小鼠中生长的同源肿瘤中分离的 NK 细胞的基因表达分析显示，在缺乏 CD226 的情况下，FOXO1 调节的基因表达失调。体外细胞毒性和刺激实验表明，CD226 是杀伤肿瘤靶细胞的最佳杀伤所必需的，其配体 CD155 的结合导致 FOXO1 的磷酸化。CD226 缺陷或抗 CD226 抗体阻断会损害细胞毒性，同时使 FOXO1 失活受损。此外，FOXO1 磷酸化抑制剂阻断了 CD226 介导的信号转导和效应反应。这些结果定义了 CD226 对 NK 细胞针对肿瘤的反应进行控制的途径。
