Ubenimex synergizes with the PD-L1 blockade in gastric cancer by competitively binding LAP3 with UBE3A

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 blockade are vital for advanced gastric cancer (GC).
• Resistance to ICIs limits their effectiveness, necessitating novel combination therapies.
• Ubenimex, an immunomodulator and leucyl aminopeptidase 3 (LAP3) inhibitor, is explored for enhancing anti-PD-L1 therapy.

Purpose of the Study:

• To investigate Ubenimex's potential to augment PD-L1 blockade efficacy in gastric cancer.
• To elucidate the role of LAP3 in GC progression and immune evasion.
• To uncover the molecular mechanism by which Ubenimex overcomes resistance to PD-L1 blockade.

Main Methods:

• Utilized a syngeneic gastric cancer mouse model.
• Assessed LAP3 expression in GC tissues and cells.
• Investigated the interaction between LAP3, UBE3A, and PD-L1.
• Evaluated CD8+ T cell infiltration and cytotoxicity in the tumor microenvironment (TME).

Main Results:

• Ubenimex significantly improved anti-PD-L1 therapy efficacy in GC.
• High LAP3 expression correlated with poor GC prognosis and impaired CD8+ T cell function.
• LAP3 enhances PD-L1 expression by binding to UBE3A, hindering PD-L1 degradation.
• Ubenimex disrupted the LAP3-UBE3A interaction, restoring PD-L1 ubiquitination and degradation, thereby enhancing anti-tumor immunity.

Conclusions:

• Ubenimex synergizes with PD-1/PD-L1 blockade to overcome resistance in gastric cancer.
• Targeting the LAP3-UBE3A interaction offers a promising therapeutic strategy for advanced GC.
• This combination therapy has the potential to improve clinical outcomes for GC patients treated with ICIs.