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Cell. 2015 Sep 24;163(1):160-73. doi: 10.1016/j.cell.2015.09.001.

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

Author information

1
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK. Electronic address: a.serrels@ed.ac.uk.
2
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
3
MRC Centre for Inflammation Research, The Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
4
Verastem Inc., 117 Kendrick Street, Suite 500, Needham, MA 02494, USA.
5
Queen Mary, University of London, Centre for Cancer and Inflammation, Charterhouse Square, London EC1M 6BQ, UK.
6
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
7
Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
8
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK. Electronic address: m.frame@ed.ac.uk.

Abstract

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.

PMID:
26406376
PMCID:
PMC4597190
DOI:
10.1016/j.cell.2015.09.001
[Indexed for MEDLINE]
Free PMC Article

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