USP22 Deubiquitinates CD274 to Suppress Anticancer Immunity

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Programmed cell death protein 1 (PD-1, CD279)-programmed death-ligand 1 (PD-L1, CD274) signaling is crucial for cancer immune evasion and a key target in immunotherapy.
• Posttranslational modifications of CD274, including ubiquitination, influence immune suppression, but deubiquitination mechanisms remain unclear.

Purpose of the Study:

• To identify novel deubiquitinases regulating CD274.
• To investigate the role of USP22 in CD274 regulation and its impact on liver cancer progression and immunotherapy.

Main Methods:

• Identified USP22 as a CD274 deubiquitinase through interaction studies.
• Analyzed USP22 expression and alterations in various cancer types, particularly liver cancer.
• Evaluated the effects of USP22 depletion on liver cancer growth, tumor immunity, and therapeutic responses in preclinical models.

Main Results:

• USP22 directly interacts with CD274, promoting its deubiquitination and stabilization.
• High USP22 expression in liver cancer correlates with poor patient prognosis.
• Genetic depletion of USP22 suppressed liver cancer growth, enhanced anti-tumor immunity, and improved responses to CD274-targeted therapy and chemotherapy.

Conclusions:

• USP22 is a novel deubiquitinase of CD274, playing a significant role in liver cancer immune evasion.
• Targeting USP22 represents a promising strategy to enhance anti-cancer immunity and potentiate immunotherapy in CD274-amplified cancers.