Pancreatic ductal adenocarcinoma (PDAC) remains a cancer with few effective
therapeutic options, and patient prognosis is poor. Immunotherapy has yet to yield
significant benefit in treatment of PDAC. Understanding the key molecular pathways
that drive resistance to immunotherapy may enable development of new therapeutic
strategies for this cancer of unmet clinical need. The non-receptor protein tyrosine
kinase, Focal Adhesion Kinase (FAK), is up-regulated in PDAC, and recent studies have
identified an important role for FAK in regulating the fibrotic and immunosuppressive
pancreatic tumour microenvironment (TME). However, the mechanisms underpinning
FAK-dependent regulation of the immunosuppressive TME remain poorly understood.
Using CRISPR, I have depleted FAK expression in pancreatic cancer cells isolated from
PDAC arising on LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice (KPC mice), and
show that FAK-depletion results in a tumour growth delay that is associated with
reprogramming of the tumour associated macrophage (TAM) phenotype.
Mechanistically I identify FAK-dependent regulation of interleukin-6 secretion from
pancreatic cancer cells as an important regulator of the TAM phenotype, and further
show that this axis requires CD4+ T-cells. These results provide new insights into the
complexity of FAK-dependent immune regulation in cancer, and support continued
evaluation of FAK kinase inhibitors in combination with immunotherapy for the
treatment of PDAC
