Disruption of Wnt/β-catenin Pathway Elevates the Sensitivity of Gastric Cancer Cells to PD-1 Antibody

Abstract

Background: Gastric Cancer (GC) is the fifth most common malignancy tumor and the third cause of cancer-related death around the world. Immune checkpoint inhibitors (ICIs) such as programmed cell death-1 (PD-1) antibodies play an active role in tumor therapy. A recent study reveals that Wnt/β-catenin signaling pathway is negatively correlated with T-cell infiltration in tumor microenvironment (TME), thereby influencing the therapeutic efficacy of PD-1 antibody.

Objective: In this study, we aimed to uncover the relationship of Wnt/β-catenin pathway to CD8+ T cell activity as well as its effect on anti-PD-1 therapeutic efficacy in GC.

Methods and results: We first collected clinical samples and went through an immunohistochemical analysis and found that a high β-catenin expression in GC tissues was often associated with a significant absence of CD8+ T-cell infiltration. In addition, our data further indicated that disruption of the Wnt/β-catenin pathway in GC cells inhibited their migratory and invasive ability. Meanwhile, enhanced sensitivity of GC cells to PD-1 blockade therapy was evident by decreased Jurkat cell apoptosis rate and increased GC cell apoptosis rate in a tumor and Jurkat cells co-culture system with the presence of Wnt/β-catenin pathway inhibition.

Conclusion: Collectively, these findings indicated Wnt/β-catenin pathway may play a significant role in modulating the activity of Jurkat cells and downregulation of Wnt/β-catenin may enhance the sensitivity of GC cells to PD-1 antibody in vitro. This result further indicated that β-catenin and PD-1 targeted inhibition might become a potential and effective therapy for GC patients.

Keywords: Gastric cancer; T-cell infiltration; immune checkpoint blockade; immunotherapy; malignant tumor; β-catenin.