Nuclear FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor Immunity

Alan Serrels,Tom Lund,Bryan Serrels,Adam Byron,Rhoanne C Mcpherson,Alexander Von Kriegsheim,Laura Gómez-Cuadrado,Marta Canel,Morwenna Muir,Jennifer E Ring,Eleni Maniati,Andrew H Sims,Jonathan A Pachter,Valerie G Brunton,Nick Gilbert,Stephen M Anderton,Robert J.B Nibbs,Margaret C Frame

doi:10.1016/j.cell.2015.09.001

Abstract

SummaryFocal 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.

Highlights

First described more than a decade ago (Onizuka et al, 1999; Shimizu et al, 1999), regulatory T cells (Tregs) have become recognized as a core component of the immuno-suppressive armory utilized by many tumors to keep the anti-tumor activity of antigen-primed CD8+ T cells at bay
Nuclear Focal adhesion kinase (FAK) is associated with chromatin and exists in complex with transcription factors and their upstream regulators that control Ccl5 expression
We show that a small-molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, drives depletion of Tregs and promotes a CD8+ T cell-mediated anti-tumor response

Summary

Introduction

First described more than a decade ago (Onizuka et al, 1999; Shimizu et al, 1999), regulatory T cells (Tregs) have become recognized as a core component of the immuno-suppressive armory utilized by many tumors to keep the anti-tumor activity of antigen-primed CD8+ T cells at bay. The ratio of CD8+ T cells/Tregs correlates with poor prognosis, shifting the balance from antitumor immunity toward tumor tolerance (Quezada et al, 2006; Sato et al, 2005; Shah et al, 2011). Through secreting a range of chemokines and cytokines, cancer cells can promote the recruitment of Tregs into tumors and can facilitate their peripheral expansion and retention (Darrasse-Jeze and Podsypanina, 2013; Ondondo et al, 2013). Tregs can act as a barrier to effective immune-based therapy aimed at activation of a CD8+ T cell anti-tumor immune response. The specific signals within tumor cells that stimulate elevated intra-tumoral Tregs, giving rise to tumor tolerance, remain elusive

Results

Discussion

Conclusion