A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model
Yuhua Wei1, Yufeng Wang1, Nanbin Liu1
1Department of General Surgery, Tongji Hospital, Tongji University Medical School, Shanghai, China.
Abstract:
Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.
Insights
Combining a FAK inhibitor (VS-4718) with anti-PD1 immunotherapy shows promise for hepatocellular carcinoma (HCC). This approach improves the tumor microenvironment and immune response, offering a potential new treatment strategy for HCC patients.
Area of Science:
- Hepatocellular Carcinoma (HCC) Research
- Cancer Immunotherapy
- Molecular Targeted Therapy
Background:
- Anti-PD-1/PD-L1 immunotherapy exhibits limited efficacy in hepatocellular carcinoma (HCC), failing to benefit all patients.
- Focal Adhesion Kinase (FAK) inhibitors, such as VS-4718, have shown potential in modulating tumor microenvironments.
Purpose of the Study:
- To investigate the combined therapeutic effect of FAK inhibitor VS-4718 and anti-PD1 therapy in a mouse model of HCC.
- To elucidate the underlying mechanisms of action for this combination therapy in HCC treatment.
Main Methods:
- Analysis of FAK expression and immune cell infiltration in human HCC using TCGA data.
- Establishment of a primary murine HCC model via protooncogene (c-Met/β-catenin) transfection.
- Evaluation of tumor pathological characteristics following treatment with VS-4718 and/or anti-PD1.
Main Results:
- High FAK expression in human HCC correlates with poor overall survival (OS) and progression-free survival (PFS).
- Combination therapy demonstrated superior efficacy compared to monotherapy in the experimental HCC model.
- VS-4718 modulated the immune microenvironment by decreasing Tregs and macrophages while increasing CD8+ T cells, and notably, promoted PD-L1 expression.
Conclusions:
- Combination of FAK inhibitor VS-4718 and anti-PD1 represents a potential therapeutic strategy for HCC.
- This combination therapy enhances the anti-tumor immune response and may reduce liver fibrosis.
- The strategy addresses increased PD-L1 expression induced by FAK inhibition, potentially overcoming resistance mechanisms.
