Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy

Abstract

Single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to 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 acts as a barrier to T-cell infiltration. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This delay in tumor progression was associated with dramatically 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.

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

“…As discussed elsewhere by in this CCR focus section, achieving significant advances in PDAC will likely require multi-modal therapeutic strategies to target the epithelial, stromal and immune components of the tumor (38,65) (73,75,76). Inhibiting the CCR2-CCL2 axis modulates both T and non-T cell immune mechanisms, potentially leading to enhanced response in combination with cytotoxic chemotherapy (74).…”

Immunotherapy in gastrointestinal cancers

“…This approach relies on manipulation on the focal adhesion kinase (FAK) pathway using the small molecule FAK inhibitors VS-4718 or defactinib. In the KPC mouse model, the addition of the small molecule FAK inhibitor VS-4718 increased response to anti-PD1 and anti-CTLA4 therapy combined with gemcitabine and significantly prolonged survival in the mouse (43). Based on this work, clinical trials using FAK inhibitors are currently underway.…”

Pancreatic cancer: a mechanobiology approach

“…In this light, a study led by DeNardo et al reports elevated FAK activity in human PDAC tissues that correlates with high levels of fibrosis and immunosuppressive tumour microenvironment via reduced CD8 + cytotoxic T cell infiltration [7]. Notably, pharmacologic inhibition of FAK decreased fibrosis and tissue stiffness, reduced tumour growth and metastasis, and decreased the number of tumour-infiltrating immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs) and regulatory T cells (Tregs).…”

“…The contribution of the desmoplastic reaction to tumour progression is currently a topic of intense debate. Indeed, studies have shown that it hampers drug delivery and promotes tumour growth and metastasis [3][4][5][6][7][8][9][10][11]; however, while some works showed that decreasing fibrosis improved drug delivery and prognosis [12], other stroma targeting approaches that attempt to completely eliminate the desmoplastic stroma have yielded underwhelming results in the clinic as exemplified by the recent failure of Hedgehog inhibitors or radical efforts to delete all stromal myofibroblasts in genetically engineered mouse models [13,14].…”