Journal
CELL
Volume 163, Issue 1, Pages 160-173Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.09.001
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Funding
- Cancer Research UK [C157/A15703]
- European Research Council [29440]
- Medical Research Council [G1100084]
- MRC [G0900992, G1100084] Funding Source: UKRI
- Cancer Research UK [15703] Funding Source: researchfish
- Medical Research Council [G1100084, G0900992] Funding Source: researchfish
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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.
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