Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy
By Hong Jiang, Samarth Hegde, B. Knolhoff, Yu Zhu, J. Herndon, M. Meyer, T. Nywening, W. Hawkins, I. Shapiro, D. Weaver and 3 more. Nature Medicine, 2016
910 citations recorded by the source corpus.
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-KrasG12D;Trp53flox/+ (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.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/0e3a3801b15e52ecb4f046c5124d8230c250666e
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Citations in the corpus
- Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “As mentioned before, the FAK signaling pathway is an important fibrosis-activated signaling pathway of CAFs involved in matrix stiffness and immune suppression [284].”
- Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features (2017, neutral): “Variable Training set (n=225) Validation Set (n=131) TCGA set (n=190) Median age (IQR) 66 (61-72) 66 (55-71) 62 (52-70) Gender, male (%) 178 (79) 96 (73) 123 (65) Etiology (%) Hepatitis C 101 (46) 64 (50) N/A Hepatitis B 48 (21) 39 (30) N/A Alcohol 33 (15) 6 (5) N/A Others 38 (17) 19 (15) Child-Pugh”
- Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance (2019, background): “Interestingly, FAK inhibition restores sensitivity to double immune checkpoint therapy in the KPC mouse model of pancreatic cancer (Jiang et al., 2016).”