Autophagy inhibition amplifies anti-tumor immunity effect of dinutuximab beta on neuroblastoma via the VEGFR/AKT/mTOR and ROS/NF-κB pathways

Abstract

Dinutuximab beta has shown limited efficacy in treating high-risk neuroblastoma (NB). Combining autophagy inhibitors with immune checkpoint inhibitors (ICIs) has proven effective in many malignancies. However, the anti-tumor effects of autophagy inhibition in conjunction with anti-GD2 immunotherapy remain unknown. In this study, dinutuximab beta induces anti-proliferation and anti-EMT activity in NB cells. Dinutuximab beta also triggers autophagy in NB cells, and inhibition of the VEGFR pathway with anlotinib amplifies dinutuximab beta-induced autophagy. In addition, dinutuximab beta induces the synthesis of the chemokine CXCL9 and the infiltration of CD8⁺ T cells. Mechanistically, dinutuximab beta inhibits the VEGFR/AKT/mTOR and ROS/NF-κB pathways. Furthermore, autophagy inhibition by CQ enhances CXCL9 expression and anti-tumor T cell responses of single anti-GD2 therapy in vitro and in vivo. Collectively, this study suggests autophagy inhibitors may be a promising strategy for enhancing therapeutic efficacy in NB in conjunction with anti-GD2 immunotherapy.

Keywords: Autophagy; CXCL9; Dinutuximab beta; Immune microenvironment; Neuroblastoma; ROS.