Serrels Alan, Lund Tom, Serrels Bryan, Byron Adam, McPherson Rhoanne C, von Kriegsheim Alexander, Gómez-Cuadrado Laura, Canel Marta, Muir Morwenna, Ring Jennifer E, Maniati Eleni, Sims Andrew H, Pachter Jonathan A, Brunton Valerie G, Gilbert Nick, Anderton Stephen M, Nibbs Robert J B, Frame Margaret C
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
Cell. 2015 Sep 24;163(1):160-73. doi: 10.1016/j.cell.2015.09.001.
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.
粘着斑激酶（FAK）促进抗肿瘤免疫逃逸。具体而言，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，包括通过关键的Ccl5转录，驱动肿瘤微环境中CD8(+) T细胞耗竭和调节性T细胞（Tregs）募集。这些变化抑制抗原致敏的细胞毒性CD8(+) T细胞活性，使表达FAK的肿瘤得以生长。从机制上讲，核FAK与染色质相关，并与控制Ccl5表达的转录因子及其上游调节因子形成复合物存在。此外，FAK的免疫调节核活性可能对癌性鳞状上皮细胞具有特异性，因为正常角质形成细胞没有核FAK。最后，我们表明，目前正在临床开发的小分子FAK激酶抑制剂VS-4718也能促使Tregs耗竭，并促进CD8(+) T细胞介导的抗肿瘤反应。因此，FAK抑制剂可能触发免疫介导的肿瘤消退，提供了以前未被认识到的治疗机会。
