Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy

Nat Med. 2016 Aug;22(8):851-60. doi: 10.1038/nm.4123. Epub 2016 Jul 4.

Abstract

Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinoma, Pancreatic Ductal / immunology*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Proliferation / drug effects
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Disease Models, Animal
  • Disease Progression
  • Fibrosis
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Immunotherapy
  • Immunotherapy, Adoptive / methods*
  • Mice
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Escape / immunology*
  • Tumor Microenvironment

Substances

  • Aminopyridines
  • Antimetabolites, Antineoplastic
  • PND 1186
  • Programmed Cell Death 1 Receptor
  • Deoxycytidine
  • gemcitabine
  • Focal Adhesion Protein-Tyrosine Kinases