FAK Promotes an Immunosuppressive PDAC Tumor Microenvironment

In pancreatic ductal adenocarcinoma (PDAC), the success of immunotherapy is limited by the uniquely immunosuppressive tumor microenvironment, which is characterized by excessive fibrosis and infiltration by immunosuppressive cells. Thus, therapies to mitigate the immunosuppressive effects of the tumor microenvironment are desired. Focal adhesion kinase 1 (FAK1) is a nonreceptor tyrosine kinase that has been implicated in inflammation and pathologic fibrosis and is associated with a poor prognosis in cancer, prompting Jiang and colleagues to investigate the role of FAK signaling in the PDAC tumor microenvironment. The majority of tumors from patients with PDAC exhibited increased levels of both total FAK1 and phospho-FAK1, and patients with high phospho-FAK1 expression exhibited reduced tumor-infiltrating CD8⁺ cytotoxic T lymphocytes (CTL), which was associated with poor clinical outcomes. Further, FAK1 activation was correlated with increased collagen I deposition, altogether indicating that FAK2 activation promotes a fibrotic and immunosuppressive microenvironment. In the KPC mouse model of PDAC, the clinically available dual FAK1/FAK2 inhibitor VS-4718 extended survival as a single-agent therapy by inducing tumor stasis (rather than tumor regression). Additionally, FAK inhibition reduced fibrosis, suggesting that the survival benefit results from simultaneous induction of PDAC stasis and stromal depletion. FAK1 knockdown reduced tumor cell growth in vivo, but not in vitro, and reduced myeloid-derived suppressor cell and tumor-associated macrophage infiltration and increased CD8⁺ CTL infiltration, suggesting that FAK1 is required to generate the fibrotic and immunosuppressive PDAC tumor microenvironment. Moreover, recent studies have indicated that stromal depletion may enhance the response to chemotherapy and immunotherapy, and, consistent with these findings, FAK inhibition improved the efficacy of chemotherapy and immunotherapy with checkpoint inhibitors in resistant mice, increasing survival. Taken together, these findings indicate that FAK signaling drives fibrosis, immunosuppression, and tumor progression in PDAC, and FAK inhibitors may prevent tumor immune evasion and enhance the efficacy of chemotherapy and immunotherapy.

Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 2016 Jul 4 [Epub ahead of print].