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

TL;DR

Ubenimex improves the effectiveness of PD-L1 blockade in gastric cancer by disrupting a protein interaction that helps cancer cells evade the immune system.

Contribution

Ubenimex synergizes with PD-L1 blockade by competitively binding LAP3 with UBE3A, offering a novel combination therapy strategy for gastric cancer.

Findings

Ubenimex enhances anti-PD-L1 therapy efficacy in a mouse model of gastric cancer.

LAP3 promotes immune evasion by impairing CD8+ T cell infiltration and increasing PD-L1 expression.

Ubenimex disrupts the LAP3-UBE3A interaction, restoring PD-L1 degradation and T cell activity.

Abstract

Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockade, represent a cornerstone of treatment for advanced gastric cancer (GC). However, their clinical efficacy is hampered by low response rates and the development of both primary and acquired resistance, underscoring the need for innovative combination therapies. In this study, we investigate the potential of Ubenimex, an immunomodulator and inhibitor of leucyl aminopeptidase 3 (LAP3), in enhancing the therapeutic efficacy of PD-L1 blockade in GC. Using a syngeneic GC mouse model, we demonstrate that Ubenimex significantly augments the efficacy of anti-PD-L1 therapy. We further explore the role of LAP3 in GC progression and find that it is highly expressed in both GC tissues and cells, with elevated LAP3 levels correlating with poor prognosis. Functionally, LAP3 facilitates immune evasion through impaired CD8+ T cell infiltration and cytotoxicity in the GC tumor microenvironment (TME). Notably, our findings reveal that LAP3 enhances PD-L1 expression by binding to UBE3A, an E3 ubiquitin ligase. Ubenimex disrupts the LAP3-UBE3A interaction, leading to restored UBE3A-mediated ubiquitination and degradation of PD-L1. This mechanism reinvigorates CD8+ T cell infiltration and cytotoxic activity within the TME, thereby overcoming resistance to anti-PD-L1 therapy. In conclusion, our study provides a strong rationale for the synergistic potential of Ubenimex in combination with PD-1/PD-L1 blockade, offering a promising strategy to overcome current limitations of ICIs therapy in GC patients.

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