eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma.
eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma.
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eEF2K 通过灭活黑色素瘤中的 GSK3β 促进 PD-L1 稳定
DOI：
10.1136/jitc-2021-004026
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Cheng Y
中科院分区：
文献类型：
--
作者：
Chen X;Wang K;Jiang S;Sun H;Che X;Zhang M;He J;Wen Y;Liao M;Li X;Zhou X;Song J;Ren X;Yi W;Yang J;Chen X;Yin M;Cheng Y
针对程序性死亡配体-1（PD-L1）/程序性细胞死亡蛋白-1（PD-1）通路的免疫检查点阻断（ICB）已成为一种有吸引力的癌症治疗策略;然而，不令人满意的疗效限制了其临床益处。因此，更全面地了解PD-L1表达的调控对于开发更有效的癌症免疫疗法至关重要。近年来研究发现，真核细胞延伸因子2激酶（eEF 2K）在促进上皮-间质转化（EMT）、血管生成、肿瘤细胞迁移和侵袭等方面具有重要作用，但其在肿瘤免疫微环境（TIME）调控中的确切作用尚不清楚。在这项研究中，我们使用了38例接受抗PD-1治疗的黑色素瘤患者队列，以探索eEF 2K表达与黑色素瘤免疫治疗疗效之间的相关性。采用免疫沉淀-质谱分析和体外实验研究eEF 2K在调节PD-L1表达中的作用和分子机制。我们还确定了eEF 2K对小鼠黑色素瘤模型中TIME中的肿瘤生长和CD 8 + T细胞的细胞毒性的影响。我们进一步研究了eEF 2K抑制与抗PD-1治疗组合的体内功效。高eEF 2K表达与PD-1单克隆抗体（mAb）治疗的黑色素瘤患者的治疗反应更好和生存期更长相关。此外，eEF 2K蛋白表达与PD-L1蛋白表达呈正相关。从机制上讲，eEF 2K通过在丝氨酸9（S9）处磷酸化糖原合成酶激酶3 β（GSK 3 β）直接结合并使其失活，导致PD-L1蛋白稳定和上调，随后导致肿瘤免疫逃避。eEF 2K的敲低降低了PD-L1表达并增强了CD 8 + T细胞活性，从而显著减弱了体内鼠B16 F10黑色素瘤生长。临床上，p-GSK 3 β/S9表达与eEF 2K和PD-L1的表达以及抗PD-1免疫治疗的应答呈正相关。此外，eEF 2K抑制剂、NH 125治疗或eEF 2K敲低增强了PD-1 mAb治疗在黑色素瘤小鼠模型中的疗效。我们的研究结果表明，eEF 2K可作为预测接受抗PD-1治疗的患者的治疗反应和预后的生物标志物，揭示了eEF 2K通过控制PD-L1表达在调节TIME中的重要作用，并提供了潜在的eEF 2K抑制与ICB治疗的联合治疗策略。
Immune checkpoint blockade (ICB) targeting programmed death ligand-1 (PD-L1)/programmed cell death protein-1 (PD-1) pathway has become an attractive strategy for cancer treatment; however, unsatisfactory efficacy has limited its clinical benefits. Therefore, a more comprehensive understanding of the regulation of PD-L1 expression is essential for developing more effective cancer immunotherapy. Recent studies have revealed the important roles of eukaryotic elongation factor 2 kinase (eEF2K) in promoting epithelial-mesenchymal transition (EMT), angiogenesis, tumor cell migration and invasion; nevertheless, the exact role of eEF2K in the regulation of tumor immune microenvironment (TIME) remains largely unknown. In this study, we used a cohort of 38 patients with melanoma who received anti-PD-1 treatment to explore the association between eEF2K expression and immunotherapy efficacy against melanoma. Immunoprecipitation-mass spectrometry analysis and in vitro assays were used to examine the role and molecular mechanism of eEF2K in regulating PD-L1 expression. We also determined the effects of eEF2K on tumor growth and cytotoxicity of CD8+ T cells in TIME in a mouse melanoma model. We further investigated the efficacy of the eEF2K inhibition in combination with anti-PD-1 treatment in vivo. High eEF2K expression is correlated with better therapeutic response and longer survival in patients with melanoma treated with PD-1 monoclonal antibody (mAb). Moreover, eEF2K protein expression is positively correlated with PD-L1 protein expression. Mechanistically, eEF2K directly bound to and inactivated glycogen synthase kinase 3 beta (GSK3β) by phosphorylating it at serine 9 (S9), leading to PD-L1 protein stabilization and upregulation, and subsequently tumor immune evasion. Knockdown of eEF2K decreased PD-L1 expression and enhanced CD8+ T cell activity, thus dramatically attenuating murine B16F10 melanoma growth in vivo. Clinically, p-GSK3β/S9 expression is positively correlated with the expressions of eEF2K and PD-L1, and the response to anti-PD-1 immunotherapy. Furthermore, eEF2K inhibitor, NH125 treatment or eEF2K knockdown enhanced the efficacy of PD-1 mAb therapy in a melanoma mouse model. Our results suggest that eEF2K may serve as a biomarker for predicting therapeutic response and prognosis in patients receiving anti-PD-1 therapy, reveal a vital role of eEF2K in regulating TIME by controlling PD-L1 expression and provide a potential combination therapeutic strategy of eEF2K inhibition with ICB therapy.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
EEF2激酶通过阻止翻译伸长来赋予对营养剥夺的耐药性。
影响因子：
64.5
作者：
Leprivier G;Remke M;Rotblat B;Dubuc A;Mateo AR;Kool M;Agnihotri S;El-Naggar A;Yu B;Somasekharan SP;Faubert B;Bridon G;Tognon CE;Mathers J;Thomas R;Li A;Barokas A;Kwok B;Bowden M;Smith S;Wu X;Korshunov A;Hielscher T;Northcott PA;Galpin JD;Ahern CA;Wang Y;McCabe MG;Collins VP;Jones RG;Pollak M;Delattre O;Gleave ME;Jan E;Pfister SM;Proud CG;Derry WB;Taylor MD;Sorensen PH
通讯作者：
Sorensen PH
eEF-2 激酶是通过控制 PP2A-A 合成来调节 Warburg 效应的关键因子
影响因子：
8
作者：
Cheng, Y.;Ren, X.;Yang, J-M
通讯作者：
Yang, J-M
EEF2K 对自噬和细胞凋亡的综合调控控制细胞命运并调节姜黄素和万卡迪对抗肿瘤细胞的功效
影响因子：
13.3
作者：
Cheng, Yan;Ren, Xingcong;Yang, Jin-Ming
通讯作者：
Yang, Jin-Ming
影响因子：
3.9
作者：
Proud, Christopher G.
通讯作者：
Proud, Christopher G.