title: Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity.
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.
authors.affiliation: 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.
authors.forename: Alan
authors.initials: A
authors.lastname: Serrels
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Lund
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Serrels
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Byron
authors.affiliation: MRC Centre for Inflammation Research, The Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Rhoanne C
authors.initials: RC
authors.lastname: McPherson
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: von Kriegsheim
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Gómez-Cuadrado
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Canel
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Morwenna
authors.initials: M
authors.lastname: Muir
authors.affiliation: Verastem Inc., 117 Kendrick Street, Suite 500, Needham, MA 02494, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ring
authors.affiliation: Queen Mary, University of London, Centre for Cancer and Inflammation, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Maniati
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.affiliation: Verastem Inc., 117 Kendrick Street, Suite 500, Needham, MA 02494, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Pachter
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Gilbert
authors.affiliation: MRC Centre for Inflammation Research, The Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
authors.affiliation: Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Robert J B
authors.initials: RJ
authors.lastname: Nibbs
authors.affiliation: 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.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014158:Transcription, Genetic; D019139:Tumor Escape
chemical_list: D000631:Aminopyridines; D018946:Chemokine CCL5; C559284:PND 1186; D051416:Focal Adhesion Protein-Tyrosine Kinases