Focal Adhesion Kinase – a new target in cancer immunotherapy
Session type: Oral
1MRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh
Immunotherapy has revolutionised the treatment of some cancers. However, many patients still do not respond. Therefore, understanding the key molecular pathways that drive resistance to immunotherapy will enable development of new therapeutic strategies. We recently identified a novel role for the non-receptor protein tyrosine kinase Focal Adhesion Kinase (FAK) in regulating the anti-tumour immune response in a mouse model of skin Squamous Cell Carcinoma (SCC). Specifically, FAK-dependent regulation of the chemokine Ccl5 was required to drive elevated numbers of regulatory T-cells into tumours, resulting in suppression of the anti-tumour CD8+ T-cell response. Regulation of Ccl5 expression was dependent on FAK nuclear function, and treatment with a small molecule FAK kinase inhibitor resulted in complete SCC tumour regression. Therefore, targeting FAK can reprogram the immuno-suppressive tumour microenvironment (TME) to potentiate an anti-tumour immune response. Similar findings have since been reported using transplantable and genetic mouse models of pancreatic cancer, identifying that treatment with a FAK kinase inhibitor can result in broad reprogramming of the fibrotic and immunosuppressive pancreatic TME. However, the mechanisms underpinning FAK-dependent regulation of the pancreatic TME are poorly characterised. We have used CRISPR to deplete FAK expression in pancreatic cancer cells isolated from PDAC arising on Pdx-cre KrasG12D/+p53R172H/+ mice (KPC mice), and show that FAK-depletion results in (1) an anti-tumour CD8+ T-cell response that contributes to an inhibition of tumour growth, (2) regulation of the immuno-suppressive pancreatic TME, and (3) regulation of chemokine and cytokine expression. Ongoing studies are aimed at better understanding the mechanisms of FAK-dependent immune evasion in pancreatic cancer, and are being performed alongside a clinical trial testing FAK inhibition in combination with anti-PD-1 in patients with pancreatic cancer, non-small cell lung cancer, and mesothelioma (clinicaltrials.gov NCT02758587).