Abstract A189: FAK inhibition induces T cell-mediated tumor regression: A novel role for nuclear FAK in controlling Tregs via transcription of cytokine networks

Abstract

Abstract It is clear that the behavior of tumors cannot be ascribed solely to cancer cell-autonomous traits that are typically monitored by tissue culture experiments. The tumor niche is composed of multiple cell types, of which only a fraction are cancer cells. It is in this context that we have discovered a completely new function of the integrin effector signaling protein Focal Adhesion Kinase (FAK) in driving anti-tumor immune evasion. Specifically, the activity of nuclear-targeted FAK in cancer cells drives recruitment and retention of intra-tumoral regulatory T-cells (Tregs) by transcriptionally regulating chemokine and cytokine ligand-receptor networks, crucially including transcription of TGFβ2 and CCL5. In turn, these changes inhibit antigen-primed cytotoxic CD8+ T-cell activity in the tumor microenvironment, permitting survival and growth of FAK-expressing tumors. We show that immune evasion requires nuclear FAK's catalytic activity and nuclear localization, and a small molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, drives depletion of Tregs and enables CD8+ T-cell-mediated tumor clearance. It is therefore likely that FAK inhibitors may trigger immune-mediated tumor regression, providing previously unrecognized therapeutic benefit. These preclinical data also suggest a novel mechanism by which a FAK inhibitor may potentiate the efficacy of checkpoint antibodies or other immunotherapeutic strategies. Citation Format: Alan Serrels, Tom Lund, Bryan Serrels, Adam Bryon, Jennifer Ring, Jonathan A Pachter, Valerie G Brunton, Robert J.B Nibbs. FAK inhibition induces T cell-mediated tumor regression: A novel role for nuclear FAK in controlling Tregs via transcription of cytokine networks. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A189.