Search

Summary 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., Graphical Abstract, Highlights • 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.