Zosuquidar Promotes Antitumor Immunity by Inducing Autophagic Degradation of PD-L1

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Programmed death-ligand 1 (PD-L1) expression is crucial for immune evasion in cancer.
• Intracellular transport mechanisms regulate PD-L1 levels and represent potential therapeutic targets.

Purpose of the Study:

• To identify modulators of PD-L1 expression through high-content screening.
• To elucidate the mechanism by which ABCB1 affects PD-L1 trafficking and degradation.

Main Methods:

• Cell-based high-content screening to identify modulators of PD-L1.
• Investigating the interaction between ABCB1 and PD-L1.
• Assessing the impact of zosuquidar on PD-L1 degradation via autophagy.
• Evaluating tumor growth and T cell infiltration in mouse models.

Main Results:

• Zosuquidar, an ABCB1 modulator, significantly reduces PD-L1 expression by inducing autophagic degradation.
• ABCB1 interacts with PD-L1, hindering its transport from the endoplasmic reticulum (ER) to the Golgi apparatus.
• Zosuquidar treatment enhances ABCB1-PD-L1 interaction, causing ER retention and subsequent SQSTM1-dependent selective autophagy of PD-L1.
• Zosuquidar suppressed tumor growth and increased cytotoxic T cell infiltration in CT26 and humanized xenograft mouse models.

Conclusions:

• ABCB1 acts as a negative regulator of PD-L1 expression.
• Zosuquidar promotes PD-L1 degradation through the autophagy pathway.
• Zosuquidar demonstrates potential as an immunotherapy agent by targeting PD-L1 in the early secretory pathway.