Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity.
Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity.
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DOI：
10.1016/j.cell.2015.09.001
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发表时间：
2015-09-24
期刊：
影响因子：
64.5
通讯作者：
Frame MC
中科院分区：
文献类型：
--
作者：
Serrels A;Lund T;Serrels B;Byron A;McPherson RC;von Kriegsheim A;Gómez-Cuadrado L;Canel M;Muir M;Ring JE;Maniati E;Sims AH;Pachter JA;Brunton VG;Gilbert N;Anderton SM;Nibbs RJ;Frame MC
粘着斑激酶（FAK）促进抗肿瘤免疫逃避。具体地，鳞状细胞癌（SCC）细胞中核靶向FAK的激酶活性通过调节趋化因子/细胞因子和配体-受体网络（包括经由Ccl 5的转录，这是至关重要的）驱动肿瘤微环境中CD 8 + T细胞的耗竭和调节性T细胞（Tcl 3）的募集。这些变化抑制抗原引发的细胞毒性CD 8 + T细胞活性，允许表达FAK的肿瘤生长。从机制上讲，核FAK与染色质相关，并与转录因子及其控制Ccl 5表达的上游调控因子复合存在。此外，FAK的免疫调节核活性可能对癌性鳞状上皮细胞是特异性的，因为正常角质形成细胞不具有核FAK。最后，我们发现，目前正在临床开发的小分子FAK激酶抑制剂VS-4718也可以驱动TcR的消耗，并促进CD 8 + T细胞介导的抗肿瘤反应。因此，FAK抑制剂可能引发免疫介导的肿瘤消退，提供以前未被认识到的治疗机会。FAK的消耗或激酶抑制可导致鳞状细胞癌消退FAK通过诱导免疫抑制性微环境促进肿瘤逃避核FAK促进趋化因子的转录，所述趋化因子驱动T细胞的募集FAK诱导的T细胞抑制细胞毒性CD 8 + T细胞，允许肿瘤耐受性和生长核粘着斑激酶（FAK）调节趋化因子的转录，趋化因子驱动肿瘤相关调节性T细胞（T细胞）的募集，从而通过抑制细胞毒性CD 8 + T细胞活性产生肿瘤抑制微环境。
Focal adhesion kinase (FAK) promotes anti-tumor immune evasion. Specifically, the kinase activity of nuclear-targeted FAK in squamous cell carcinoma (SCC) cells drives exhaustion of CD8+ T cells and recruitment of regulatory T cells (Tregs) in the tumor microenvironment by regulating chemokine/cytokine and ligand-receptor networks, including via transcription of Ccl5, which is crucial. These changes inhibit antigen-primed cytotoxic CD8+ T cell activity, permitting growth of FAK-expressing tumors. Mechanistically, nuclear FAK is associated with chromatin and exists in complex with transcription factors and their upstream regulators that control Ccl5 expression. Furthermore, FAK’s immuno-modulatory nuclear activities may be specific to cancerous squamous epithelial cells, as normal keratinocytes do not have nuclear FAK. Finally, we show that a small-molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, also drives depletion of Tregs and promotes a CD8+ T cell-mediated anti-tumor response. Therefore, FAK inhibitors may trigger immune-mediated tumor regression, providing previously unrecognized therapeutic opportunities. Depletion or kinase inhibition of FAK can cause squamous cell carcinoma regression FAK promotes tumor evasion by inducing an immuno-suppressive microenvironment Nuclear FAK promotes transcription of chemokines that drive recruitment of Tregs FAK-induced Tregs inhibit cytotoxic CD8+ T cells, allowing tumor tolerance and growth Nuclear focal adhesion kinase (FAK) regulates transcription of chemokines that drive recruitment of tumor-associated regulatory T cells (Tregs), thereby creating a tumor suppressive microenvironment by inhibiting cytotoxic CD8+ T cell activity.