APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression.

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• APOBEC3B (A3B) is upregulated in hepatocellular carcinoma (HCC) but APOBEC mutation patterns are absent.
• The role of A3B in HCC progression and its underlying mechanisms are not fully understood.

Purpose of the Study:

• To elucidate the mechanisms of A3B upregulation in HCC.
• To investigate the influence of A3B on HCC progression and the tumor microenvironment.
• To explore the potential of targeting A3B in HCC immunotherapy.

Main Methods:

• Luciferase reporter assays to study A3B promoter activity.
• Cellular and mouse models (immunocompetent and immune-deficient) of HCC with A3B overexpression or knockdown.
• RNA-sequencing, flow cytometry, and immunohistochemistry to analyze immune cell infiltration and cytokine modulation.
• Pharmacological inhibition of CCR2 to assess the role of TAMs and MDSCs.

Main Results:

• A3B upregulation, driven by non-classical NF-κB signaling, promotes HCC growth in immunocompetent mice.
• Increased myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) were observed in A3B-expressing tumors.
• A3B interacts with Polycomb Repressor Complex 2 (PRC2), reducing H3K27me3 at the CCL2 promoter, which enhances TAM and MDSC recruitment.
• CCR2 antagonism reduced TAM and MDSC infiltration and tumor growth.

Conclusions:

• A3B plays a deaminase-independent role in shaping the HCC tumor microenvironment.
• A3B modulates immune cell infiltration, specifically TAMs and MDSCs, contributing to HCC progression.
• Targeting A3B presents a potential therapeutic strategy for HCC immunotherapy.