CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1.
CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1.
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DOI：
10.1073/pnas.1814052115
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发表时间：
2018-12-11
影响因子：
11.1
通讯作者：
Chiang EY
中科院分区：
文献类型：
--
作者：
Du X;de Almeida P;Manieri N;de Almeida Nagata D;Wu TD;Harden Bowles K;Arumugam V;Schartner J;Cubas R;Mittman S;Javinal V;Anderson KR;Warming S;Grogan JL;Chiang EY
CD 226是一种重要的活化受体，参与介导自然杀伤（NK）细胞对肿瘤的应答，但CD 226如何控制NK细胞功能尚未完全了解。CD 226属于脊髓灰质炎病毒受体（PVR）-连接蛋白家族，其包括TIGIT和CD 96，其中TIGIT作为T细胞和NK细胞抗肿瘤应答中的关键检查点以及作为免疫治疗靶标而备受关注。因此，必须确定CD 226如何抵消TIGIT和CD 96的作用，其与TIGIT和CD 96竞争结合其配体如CD 155（PVR）。我们证明，CD 155的CD 226接合是转录因子FOXO 1磷酸化所必需的，导致其对NK细胞效应器功能的负调控控制失活。肿瘤细胞的自然杀伤（NK）细胞识别通过活化受体如CD 226介导，效应子功能的抑制通常由负调控转录因子如FOXO 1控制。在这里，我们表明，CD 226调节NK细胞的细胞毒性是通过FOXO 1的失活促进。从野生型或CD 226缺陷小鼠中生长的同基因肿瘤中分离的NK细胞的基因表达分析显示，在不存在CD 226的情况下，FOXO 1调节基因的表达失调。体外细胞毒性和刺激试验表明，CD 226是最佳杀伤肿瘤靶细胞所必需的，其配体CD 155的参与导致FOXO 1的磷酸化。CD 226缺陷或抗CD 226抗体阻断损害细胞毒性，同时损害FOXO 1的失活。此外，FOXO 1磷酸化抑制剂消除了CD 226介导的信号传导和效应器反应。这些结果定义了CD 226控制NK细胞抗肿瘤反应的途径。
CD226 is an important activating receptor involved in mediating natural killer (NK) cell responses against tumors, but how CD226 exerts control over NK cell function is not fully understood. CD226 belongs to the poliovirus receptor (PVR)-nectin family that includes TIGIT and CD96, with TIGIT garnering much attention as a key checkpoint in T cell and NK cell antitumor responses and as an immunotherapy target. Thus, it is imperative to determine how CD226 counteracts the actions of TIGIT and CD96 with which it competes for binding to its ligands such as CD155 (PVR). We demonstrate that CD226 engagement of CD155 is required for phosphorylation of transcription factor FOXO1, resulting in inactivation of its negative regulatory control over NK cell effector function. 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.
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影响因子：
48
作者：
Anderson KR;Haeussler M;Watanabe C;Janakiraman V;Lund J;Modrusan Z;Stinson J;Bei Q;Buechler A;Yu C;Thamminana SR;Tam L;Sowick MA;Alcantar T;O'Neil N;Li J;Ta L;Lima L;Roose-Girma M;Rairdan X;Durinck S;Warming S
通讯作者：
Warming S
影响因子：
4.8
作者：
Kwon, Hyung-Joon;Kwon, Soon Jae;Kim, Hun Sik
通讯作者：
Kim, Hun Sik
影响因子：
32.4
作者：
Kim MV;Ouyang W;Liao W;Zhang MQ;Li MO
通讯作者：
Li MO
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
50.3
作者：
Johnston, Robert J.;Comps-Agrar, Laetitia;Grogan, Jane L.
通讯作者：
Grogan, Jane L.