CDC34 suppresses macrophage phagocytic activity and predicts poor response to immune checkpoint inhibitor in cancers

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Cell Division Cycle 34 (CDC34) is an E2 ubiquitin-conjugating enzyme involved in protein degradation and stabilization.
• CDC34 has been implicated in promoting carcinogenesis, including stabilizing epidermal growth factor receptor.

Purpose of the Study:

• To investigate the role of CDC34 in cancer progression and immune evasion across various cancer types.
• To explore CDC34 as a potential therapeutic target for enhancing immunotherapy efficacy.

Main Methods:

• Pan-cancer analysis of The Cancer Genome Atlas (TCGA) datasets.
• Single-cell RNA-sequencing analysis to assess CDC34's role in macrophage activity.
• Murine models to evaluate CDC34 inhibition and combination therapy with anti-PD-L1.
• Analysis of patient samples for correlations between CDC34, CD47, T-cell infiltration, and immunotherapy response.

Main Results:

• High CDC34 expression was observed in breast cancer, associated with poor patient outcomes.
• CDC34 negatively impacts macrophage phagocytosis by stabilizing hypoxia-inducible factor 1α (HIF1α) and upregulating CD47 in cancer cells.
• CDC34 inhibition reduced tumor growth and synergized with anti-PD-L1 therapy in mice.
• CDC34 overexpression correlated with CD47 and reduced CD8+ T-cell infiltration in patients.
• Non-responders to immunotherapy showed higher CDC34 levels and lower CD8+ T-cell infiltration.

Conclusions:

• CDC34 plays a critical role in cancer immune evasion by promoting CD47-mediated phagocytosis resistance.
• Targeting CDC34 may be a viable strategy to improve outcomes for patients resistant to immune checkpoint inhibitors.
• Combined targeting of CDC34 and PD-L1 demonstrates therapeutic potential in preclinical models.