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

Cell. 2015 Sep 24;163(1):160-73. doi: 10.1016/j.cell.2015.09.001.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / administration & dosage
  • Animals
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / metabolism
  • Chemokine CCL5 / genetics*
  • Chemokine CCL5 / immunology
  • Disease Models, Animal
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Focal Adhesion Protein-Tyrosine Kinases / genetics
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Humans
  • Keratinocytes / metabolism
  • Mice
  • Mice, Nude
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Transcription, Genetic
  • Tumor Escape*

Substances

  • Aminopyridines
  • Chemokine CCL5
  • PND 1186
  • Focal Adhesion Protein-Tyrosine Kinases

Associated data

  • GEO/GSE71662