Focal Adhesion Kinase (FAK)-Dependent Immune Escape in Hepatocellular Carcinoma

Background and Aims: Overcoming resistance to immunotherapy is an unmet medical need in the treatment of hepatocellular carcinoma (HCC). Immune-excluded HCCs are often characterized by overexpression of focal adhesion kinase (FAK) due to hypomethylation or amplification of its gene PTK2. The functional role of FAK in this tumor immune escape in HCC is poorly understood.

Methods: We applied imaging mass cytometry (IMC) to characterize the immune landscape in HCC with FAK overexpression. Moreover, human HCC single-cell RNAseq data (scRNAseq, GSE151530) were studied to determine specific lineages and differentiation states of immune cell populations associated with high or low FAK expression in tumor cells. Ex vivo spheroid perturbation studies were used to test functional effects of FAK inhibition on common molecular mechanisms of tumor immune escape.

Results: Four out of 12 human HCC tumor tissues showed markedly enhanced expression of FAK in tumor cells. High dimensional immune cell profiling by IMC indicated an increased ratio of PD1+CD4+T cells (p=0.04) and CD68+macrophages (p=0.02) in FAKhigh HCCs. Moreover, exhausted T cells such as CD39+CD8+and TIM3+CD8+were more abundant in HCCs with high FAK expression (p=0.04). Consistently, scRNAseq analyses revealed an enrichment of FOXP3+Tregs and CD163+tumor associated macrophages in FAK-overexpressing HCC tumors. Inhibition of FAK in HCC spheroids resulted in an increased expression of pro-inflammatory cytokines (e.g. CCL5) and increased MHC-class I antigen expression.

Conclusions: These data suggest FAK as a potentially targetable driver of immune escape in hepatocellular carcinoma.

Publication History

Article published online:
20 January 2025