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| Status |
Public on Nov 21, 2015 |
| Title |
Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
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.
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| Overall design |
We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
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| Contributor(s) |
Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon J, Leu E, Hawkins W, Shapiro IM, Weaver DT, Pachter JA, Wang-Gillam A, DeNardo D |
| Citation(s) |
27376576, 31076405 |
| Submission date |
Nov 20, 2015 |
| Last update date |
Apr 27, 2020 |
| Contact name |
David DeNardo |
| E-mail(s) |
DDENARDO@DOM.wustl.edu
|
| Organization name |
Washington University in St. louis
|
| Street address |
425 S. Euclid Avenue
|
| City |
Saint Louis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (1) |
| GPL21163 |
Agilent-074809 SurePrint G3 Mouse GE v2 8x60K Microarray [Probe Name version] |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA302854 |
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