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.

Note:
Funding Information: This work was supported by the National Key Research and Development Program of China (2018YFC1313000, 2018YFC1313001), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A), and Tianjin health research project (NO. TJWJ2021MS010).

Declaration of Interests: None.

Ethics Approval Statement: All animal experiments were conducted following the Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the Cancer Institute and Hospital of Tianjin Medical University (AE-2021112).

Keywords: Dinutuximab beta, Neuroblastoma, Autophagy, Immune microenvironment, ROS, CXCL9