Autophagy inhibition amplifies anti-tumor immunity effect of dinutuximab beta on neuroblastoma via the VEGFR/AKT/mTOR...

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Dinutuximab beta shows limited efficacy in high-risk neuroblastoma (NB).
• Autophagy inhibitors combined with immune checkpoint inhibitors (ICIs) are effective in various cancers.
• The combined effect of autophagy inhibition and anti-GD2 immunotherapy in NB is unexplored.

Purpose of the Study:

• To investigate the anti-tumor effects of combining autophagy inhibition with anti-GD2 immunotherapy (dinutuximab beta) in neuroblastoma.
• To elucidate the mechanisms underlying the combined therapeutic effects.

Main Methods:

• Neuroblastoma cells were treated with dinutuximab beta and anlotinib (VEGFR inhibitor) or chloroquine (CQ, autophagy inhibitor).
• Assessed anti-proliferation, anti-EMT activity, autophagy induction, chemokine (CXCL9) synthesis, and CD8+ T cell infiltration.
• Investigated the roles of VEGFR/AKT/mTOR and ROS/NF-κB pathways.

Main Results:

• Dinutuximab beta demonstrated anti-proliferative and anti-EMT effects, inducing autophagy in NB cells.
• Anlotinib amplified dinutuximab beta-induced autophagy.
• Dinutuximab beta increased CXCL9 and CD8+ T cell infiltration by inhibiting VEGFR/AKT/mTOR and ROS/NF-κB pathways.
• Autophagy inhibition with CQ enhanced CXCL9 expression and anti-tumor T cell responses.

Conclusions:

• Autophagy inhibition potentiates the anti-tumor effects of dinutuximab beta in neuroblastoma.
• Combining autophagy inhibitors with anti-GD2 immunotherapy is a promising strategy to enhance therapeutic efficacy in NB.
• Targeting autophagy may overcome limitations of current anti-GD2 therapies.