CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity.
CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity.
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DOI：
10.1038/nature23643
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发表时间：
2017-09-07
期刊：
影响因子：
64.8
通讯作者：
Dawson MA
中科院分区：
文献类型：
--
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
癌细胞利用程序性死亡-1（PD-1）配体1（PD-L1）的表达来破坏T细胞介导的免疫监视。破坏PD-L1介导的肿瘤耐受性的疗法的成功突出了理解PD-L1表达的分子调控的需要。使用全基因组CRISPR/Cas9筛选，我们确定了未表征的蛋白质CMTM 6是广泛癌细胞中PD-L1的关键调节因子。CMTM 6是一种广泛表达的蛋白质，可结合PD-L1并维持其细胞表面表达。CMTM 6不是PD-L1成熟所必需的，但与PD-L1共定位在质膜和再循环内体中，在那里它阻止PD-L1被靶向溶酶体介导的降解。使用定量方法分析整个质膜蛋白质组，我们发现CMTM 6对PD-L1显示出显着的特异性。重要的是，CMTM 6耗竭降低PD-L1而不损害I类MHC的细胞表面表达。通过减少PD-L1，CMTM 6消耗显著增强了体外和体内肿瘤特异性T细胞活性的抑制。这些发现为PD-L1调节的生物学提供了新的见解，确定了这一关键免疫检查点的先前未被识别的主调节因子，并突出了一个新的潜在治疗靶点，以克服肿瘤细胞的免疫逃避。
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell mediated immunosurveillance. The success of therapies that disrupt PD-L1 mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. Using a genome-wide CRISPR/Cas9 screen we identified the uncharacterized protein CMTM6 to be a critical regulator of PD-L1 in a broad range of cancer cells. CMTM6 is a ubiquitously expressed, protein that binds PD-L1 and maintains its cell surface expression. CMTM6 is not required for PD-L1 maturation but co-localizes with PD-L1 at the plasma membrane and in recycling endosomes where it prevents PD-L1 from being targeted for lysosome-mediated degradation. Using a quantitative approach to profile the entire plasma membrane proteome we find that CMTM6 displays remarkable specificity for PD-L1. Importantly, CMTM6 depletion decreases PD-L1 without compromising cell surface expression of MHC Class I. CMTM6 depletion, via the reduction of PD-L1, significantly alleviates the suppression of tumour specific T-cell activity in vitro and in vivo. These findings provide novel insights into the biology of PD-L1 regulation, identify a previously unrecognised master regulator of this critical immune checkpoint and highlight a new potential therapeutic target to overcome immune evasion by tumour cells.
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DOI：
10.1126/science.1235047
发表时间：
2013-04-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Weekes MP;Tan SY;Poole E;Talbot S;Antrobus R;Smith DL;Montag C;Gygi SP;Sinclair JH;Lehner PJ
通讯作者：
Lehner PJ
DOI：
10.1111/j.1600-0854.2012.01327.x
发表时间：
2012-04
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Arjonen A;Alanko J;Veltel S;Ivaska J
通讯作者：
Ivaska J
影响因子：
20.3
作者：
Green, Michael R.;Monti, Stefano;Shipp, Margaret A.
通讯作者：
Shipp, Margaret A.
影响因子：
6.6
作者：
van Weert, AWM;Geuze, HJ;Stoorvogel, W
通讯作者：
Stoorvogel, W
PD-1检查点途径的分子和生化方面。
DOI：
10.1056/nejmra1514296
发表时间：
2016-11-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Boussiotis VA
通讯作者：
Boussiotis VA