Super-enhancer receives signals from the extracellular matrix to induce PD-L1-mediated immune evasion via integrin/BRAF/TAK1/ERK/ETV4 signaling.
Super-enhancer receives signals from the extracellular matrix to induce PD-L1-mediated immune evasion via integrin/BRAF/TAK1/ERK/ETV4 signaling.
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超级增强子接收来自细胞外基质的信号，通过整合素/BRAF/TAK1/ERK/ETV4信号传导诱导PD-L1介导的免疫逃避
DOI：
10.20892/j.issn.2095-3941.2021.0137
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发表时间：
2021-10-09
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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作者：
PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpoint blockade. The factors that drive inducible PD-L1 expression have been extensively studied, but mechanisms that result in constitutive PD-L1 expression in cancer cells are largely unknown. DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout. Protein function was inhibited by chemical inhibitors. Protein levels were examined by Western blot, mRNA levels were examined by real-time RT-PCR, and surface protein expression was determined by cellular immunofluorescence and flow cytometry. Immune evasion was examined by in vitro T cell-mediated killing. We determined the core regions (chr9: 5, 496, 378–5, 499, 663) of a previously identified PD-L1L2-super-enhancer (SE). Through systematic analysis, we found that the E26 transformation-specific (ETS) variant transcription factor (ETV4) bound to this core DNA region but not to DNA surrounding PD-L1L2SE. Genetic knockout of ETV4 dramatically reduced the expressions of both PD-L1 and PD-L2. ETV4 transcription was dependent on ERK activation, and BRAF/TAK1-induced ERK activation was dependent on extracellular signaling from αvβ3 integrin, which profoundly affected ETV4 transcription and PD-L1/L2 expression. Genetic silencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible to T cell-mediated killing. We identified a pathway originating from the extracellular matrix that signaled via integrin/BRAF/TAK1/ERK/ETV4 to PD-L1L2-SE to induce PD-L1-mediated immune evasion. These results provided new insights into PD-L1L2-SE activation and pathways associated with immune checkpoint regulation in cancer.
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DOI：
10.1158/1078-0432.ccr-15-1125
发表时间：
2016-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Loi S;Dushyanthen S;Beavis PA;Salgado R;Denkert C;Savas P;Combs S;Rimm DL;Giltnane JM;Estrada MV;Sánchez V;Sanders ME;Cook RS;Pilkinton MA;Mallal SA;Wang K;Miller VA;Stephens PJ;Yelensky R;Doimi FD;Gómez H;Ryzhov SV;Darcy PK;Arteaga CL;Balko JM
通讯作者：
Balko JM
影响因子：
10.9
作者：
Mushtaq MU;Papadas A;Pagenkopf A;Flietner E;Morrow Z;Chaudhary SG;Asimakopoulos F
通讯作者：
Asimakopoulos F
影响因子：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira
影响因子：
3.6
作者：
Messal, Nassima;Serriari, Nacer-Eddine;Olive, Daniel
通讯作者：
Olive, Daniel
DOI：
10.1074/mcp.m111.014647
发表时间：
2012-04
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Naba A;Clauser KR;Hoersch S;Liu H;Carr SA;Hynes RO
通讯作者：
Hynes RO