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

Serrels, A. et al. (2015) Nuclear FAK controls chemokine transcription, tregs, and evasion of anti-tumor immunity. Cell, 163(1), pp. 160-173. (doi: 10.1016/j.cell.2015.09.001) (PMID:26406376) (PMCID:PMC4597190)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nibbs, Professor Rob
Authors: Serrels, A., Lund, T., Serrels, B., Byron, A., McPherson, R. C., von Kriegsheim, A., Gómez-Cuadrado, L., Canel, M., Muir, M., Ring, J. E., Maniati, E., Sims, A. H., Pachter, J. A., Brunton, V. G., Gilbert, N., Anderton, S. M., Nibbs, R. J.B., and Frame, M. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell
Publisher:Cell Press
ISSN:0092-8674
ISSN (Online):1097-4172
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Cell 163(1):160-173
Publisher Policy:Reproduced under a Creative Commons License

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