A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model

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.

Loss of MTA2‐mediated downregulation of PTK7 inhibits hepatocellular carcinoma metastasis progression by modulating the FAK‐MMP7 axis

“…PRL‐3 is significantly overexpressed and contributes to HCC malignant behaviors via the FAK signaling pathway 34 . FAK inhibitor was shown to promote PD‐L1 expression and boost anti‐PD1 immunotherapy in an HCC mouse model 35 . In our study, FAK was shown to mediate PTK7‐regulated MMP7 expression and subsequent HCC cell migration and invasion abilities, and provide the insight into FAK plays a critical role in PTK7‐mediated HCC development.…”

“…34 FAK inhibitor was shown to promote PD-L1 expression and boost anti-PD1 immunotherapy in an HCC mouse model. 35 In our study, FAK was shown to mediate PTK7-regulated MMP7 expression and subsequent HCC cell migration and invasion abilities, and provide the insight into FAK plays a critical role in PTK7-mediated HCC development. Overall, our results suggest that PTK7 plays an essential role in HCC metastasis progression via targeting the FAK-MMP7 pathways.…”

Roles and inhibitors of FAK in cancer: current advances and future directions

“…Simultaneously, it facilitated T cell infiltration leading to an enhancement in the therapeutic outcomes of immune-based interventions for pancreatic cancer ( Blair et al, 2022 ). Combining the FAK inhibitors with anti-PD-1antibodies demonstrated enhanced anti-cancer effects in C57BL/6 J primary hepatocellular carcinoma model with complete immune function, reducing Tregs and TAMs while increasing CD8 + T cell population ( Wei et al, 2021 ). FAK also impedes antigen the processing and presentation in pancreatic cancer, contributing to immune evasion of pancreatic cancer.…”

“…FAK stands out as a key player in cancer pathogenesis, being abnormally activated across various cancer types. Its expression level not only is inversely linked to patient survival but also positions FAK as a pivotal target for thwarting tumor progression and curbing recurrence ( Zeng et al, 2016 ; Kanteti et al, 2018 ; Aboubakar et al, 2019a ; Aboubakar et al, 2019b ; Qiao et al, 2020 ; Wei et al, 2021 ; Roy-Luzarraga et al, 2022 ). Rigorous meta-analyses underscore the significance of heightened FAK expression in predicting unfavorable overall survival (OS) outcomes in a spectrum of solid tumors.…”

Focal adhesion kinase: from biological functions to therapeutic strategies

“…Combining the FAK inhibitor VS4718 with anti-PD1 therapy in hepatocellular carcinoma resulted in decreased macrophage numbers and increased CD8+ T-cell numbers [ 141 ]. Additionally, when FAK inhibitors were combined with agents that induce T-cell costimulatory pathways in skin squamous cell carcinoma, the tumors became more sensitive to FAK inhibitors, and this effect was mediated by CD80.…”