RT info:eu-repo/semantics/article
T1 Nuclear FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor Immunity
A1 Serrels, Alan
A1 Lund, Tom
A1 Serrels, Bryan
A1 Byron, Adam
A1 McPherson, Rhoanne C.
A1 Kriegsheim, Alexander von
A1 Gómez Cuadrado, Laura
A1 Canel, Marta
A1 Muir, Morwenna
A1 Ring, Jennifer E.
A1 Maniati, Eleni
A1 Sims, Andrew H.
A1 Patcher, Jonathan A.
A1 Brunton, Valerie G.
A1 Gilbert, Nick
A1 Anderton, Stephen M.
A1 Nibbs, Robert J.B.
A1 Frame, Margaret C.
K1 Medicina
K1 Medicine
K1 Química orgánica
K1 Chemistry, Organic
K1 Salud
K1 Health
AB 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.
PB Elsevier
SN 0092-8674
YR 2015
FD 2015-09
LK http://hdl.handle.net/10259/9790
UL http://hdl.handle.net/10259/9790
LA eng
NO This work was supported by Cancer Research UK (Grant no. C157/A15703 to M.C.F.), European Research Council (Grant no. 29440 Cancer Innovation to M.C.F.) and Medical Research Council (Grant no. G1100084 to S.M.A.). A.v.K was supported by Science Foundation Ireland under grant numbers 06/CE/B1129 and 13/SIRG/2174.
DS Repositorio Institucional de la Universidad de Burgos
RD 22-dic-2024