ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation.
ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation.
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DOI：
10.1016/j.celrep.2018.06.066
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发表时间：
2018-07-17
期刊：
影响因子：
8.8
通讯作者：
Ng T
中科院分区：
文献类型：
--
作者：
Monypenny J;Milewicz H;Flores-Borja F;Weitsman G;Cheung A;Chowdhury R;Burgoyne T;Arulappu A;Lawler K;Barber PR;Vicencio JM;Keppler M;Wulaningsih W;Davidson SM;Fraternali F;Woodman N;Turmaine M;Gillett C;Franz D;Quezada SA;Futter CE;Von Kriegsheim A;Kolch W;Vojnovic B;Carlton JG;Ng T
免疫抑制性跨膜蛋白PD-L1显示通过多泡体（MVB）运输并在外来体上释放。高含量siRNA筛选鉴定了转运所需的内体分选复合物（ESCRT）相关蛋白阿利克斯作为基底样乳腺癌（BLBC）细胞中EGFR活性和PD-L1表面呈递的调节剂。阿利克斯耗竭导致刺激诱导的EGFR活性延长和增强以及通过MVB的PD-L1运输缺陷、外泌体分泌减少及其重新分布至细胞表面。增加的表面PD-L1表达赋予ALIX耗竭细胞EGFR依赖性免疫抑制表型。在人类乳腺癌组织中观察到阿利克斯和PD-L1表达之间的负相关，而乳腺癌的免疫活性小鼠模型显示，ALIX缺陷的肿瘤更大，并且显示出增加的免疫抑制环境。我们的数据表明，阿利克斯通过调节PD-L1和EGFR来调节免疫抑制，因此可能是BLBC的诊断和治疗靶点。阿利克斯调节乳腺癌细胞中EGFR活性和PD-L1表面呈递。PD-L1被包装到乳腺癌细胞的外泌体中。阿利克斯耗竭导致外泌体减少和表面PD-L1表达增加。显示ESCRT相关蛋白阿利克斯调节乳腺癌中两种临床上重要的蛋白质;即EGFR，一种与细胞存活相关的受体，和PD-L1，一种免疫检查点蛋白。因此，阿利克斯与驱动肿瘤存活的细胞自主和非细胞自主机制的途径相关。
The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and to be released on exosomes. A high-content siRNA screen identified the endosomal sorting complexes required for transport (ESCRT)-associated protein ALIX as a regulator of both EGFR activity and PD-L1 surface presentation in basal-like breast cancer (BLBC) cells. ALIX depletion results in prolonged and enhanced stimulation-induced EGFR activity as well as defective PD-L1 trafficking through the MVB, reduced exosomal secretion, and its redistribution to the cell surface. Increased surface PD-L1 expression confers an EGFR-dependent immunosuppressive phenotype on ALIX-depleted cells. An inverse association between ALIX and PD-L1 expression was observed in human breast cancer tissues, while an immunocompetent mouse model of breast cancer revealed that ALIX-deficient tumors are larger and show an increased immunosuppressive environment. Our data suggest that ALIX modulates immunosuppression through regulation of PD-L1 and EGFR and may, therefore, present a diagnostic and therapeutic target for BLBC. ALIX regulates EGFR activity and PD-L1 surface presentation in breast cancer cells PD-L1 is packaged into the exosomes of breast cancer cells ALIX depletion results in reduced exosomal and increased surface PD-L1 expression Increased surface PD-L1 is associated with an enhanced immunosuppressive phenotype Monypenny et al. show that the ESCRT-related protein ALIX regulates two clinically important proteins in breast cancer; namely, EGFR, a receptor linked to cell survival, and PD-L1, an immune checkpoint protein. ALIX is, therefore, associated with pathways that drive both cell-autonomous and non-cell-autonomous mechanisms of tumor survival.
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影响因子：
4.8
作者：
Hashimoto, Y;Katayama, H;Matsuda, M
通讯作者：
Matsuda, M
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
3.8
作者：
Masuda, Hiroko;Zhang, Dongwei;Bartholomeusz, Chandra;Doihara, Hiroyoshi;Hortobagyi, Gabriel N.;Ueno, Naoto T.
通讯作者：
Ueno, Naoto T.
DOI：
10.1186/s13058-015-0561-8
发表时间：
2015-04-09
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Nuciforo P;Radosevic-Robin N;Ng T;Scaltriti M
通讯作者：
Scaltriti M
影响因子：
45.3
作者：
Carey, Lisa A.;Rugo, Hope S.;Winer, Eric P.
通讯作者：
Winer, Eric P.