Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity

Alan Serrels, Tom Lund, Bryan Serrels, Adam Byron, Rhoanne C. McPherson, Alex von Kriegsheim, Laura Gómez-Cuadrado, Marta Canel, Morwenna Muir, Jennifer E. Ring, Eleni Maniati, Andrew H. Sims, Jonathan A. Pachter, Valerie G. Brunton, Nick Gilbert, Stephen M. Anderton, Robert J. Nibbs, Margaret C. Frame

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)160-173
Number of pages14
Issue number1
Publication statusPublished - 24 Sept 2015


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