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oai:riubu.ubu.es:10259/97902024-12-18T01:05:15Zcom_10259_6168com_10259_5086com_10259_2604col_10259_6169

00925njm 22002777a 4500 dc Serrels, Alan author Lund, Tom author Serrels, Bryan author Byron, Adam author McPherson, Rhoanne C. author Kriegsheim, Alexander von author Gómez Cuadrado, Laura author Canel, Marta author Muir, Morwenna author Ring, Jennifer E. author Maniati, Eleni author Sims, Andrew H. author Patcher, Jonathan A. author Brunton, Valerie G. author Gilbert, Nick author Anderton, Stephen M. author Nibbs, Robert J.B. author Frame, Margaret C. author 2015-09 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. 0092-8674 http://hdl.handle.net/10259/9790 10.1016/j.cell.2015.09.001 Nuclear FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor Immunity