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-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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Acknowledgements
KC (KrasG12D) cells were obtained from P. Mukherjee (University of North Carolina). HPNE, HPAC, Capan-1, Capan-2, Hs766T, MIA PaCa-2 and SW1990 cells were obtained from K. Lim (Washington University). pBABEpuro K-Ras G12V used to express KrasG12V was obtained from J. Weber (Washington University). This work was supported by funding awarded to D.G.D. by Lustgarten Foundation, an AACR/PANCAN Award, NCI awards R01-CA177670, R01-CA203890 and R21-CA182701, the BJCIH/Siteman Cancer Center Cancer Frontier Fund, and Washington University Clinical and Translational Grant KL2TR000450 awarded to A.W.G.
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D.G.D. managed the project and coordinated activities from all authors. H.J. conducted transgenic and transplant mouse experiments and treatments. B.L.K. and J.M.H. aided with FAK inhibitor treatments. D.G.D., H.J. and B.L.K. designed experiments and provided KPC, KPPC and KPC-Y mice. D.G.D., S.H. and J.M.H. performed histology, immunofluorescence on human samples and related analyses. H.J. and S.H. conducted experiments with the PA hydrogels. H.J. performed MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide), three-dimensional collagen assays, cytokine arrays, leukocyte trafficking, immunoblotting and related analyses. S.H. and J.M.H. performed immunofluorescence and H.J. conducted analysis. H.J. and B.L.K. conducted subcutaneous and orthotropic PDAC mouse experiments. S.H. and H.J. conducted adoptive cell transfer and bioluminescence tracking. Y.Z. performed reverse transcription PCR and flow analysis in bone marrow macrophage experiments. M.A.M. performed bone marrow flow analysis. D.G.D. and H.J. conducted PDAC tumor grading in transgenic mice. T.M.N., W.G.H. and A.W.-G. collected human samples and aided with pathological pancreatic cancer scoring of human samples. I.M.S., D.T.W. and J.A.P. provided FAK inhibitor VS-4718 and VS-116, as well as expert guidance and intellectual input on the project. D.G.D., H.J. and S.H. wrote the manuscript with input from all authors.
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I.M.S., D.T.W. and J.A.P. are employees of Verastem, Inc.
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Jiang, H., Hegde, S., Knolhoff, B. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22, 851–860 (2016). https://doi.org/10.1038/nm.4123
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DOI: https://doi.org/10.1038/nm.4123
