Core Fucosylation Represses SMURF1-Dependent Degradation of CD47 to Promote Tumor Immune Evasion

Area of Science:

• Immunology
• Glycobiology
• Cancer Biology

Background:

• Glycosylation is crucial for biological processes, but its role in tumor immune escape is unclear.
• Altered glycosylation in the tumor microenvironment promotes immune evasion.
• Cluster of Differentiation 47 (CD47) is an innate immune checkpoint protein implicated in tumor immune escape.

Purpose of the Study:

• To elucidate the molecular mechanisms by which glycosylation regulates tumor immune escape via CD47.
• To investigate the role of core fucosylation of CD47 in hepatocellular carcinoma (HCC).
• To explore targeting the glycosylation pathway as a therapeutic strategy against HCC.

Main Methods:

• Analysis of CD47 glycosylation patterns in tumor cells.
• Investigating the effect of fucosyltransferase 8 (FUT8) inhibition on CD47 expression and ubiquitination.
• Utilizing a murine HCC model to assess the impact of N111 glycosylation blockade on immune cell infiltration and tumor growth.
• Evaluating combination therapy with core fucosylation inhibitors and anti-CD47 antibodies.
• Correlating FUT8 levels with CD47 expression and immune cell infiltration in human HCC specimens.

Main Results:

• Core fucosylation of CD47 at N111 by FUT8 reduces its ubiquitination and degradation, leading to increased expression.
• Blocking N111 glycosylation represses CD47 expression, enhancing macrophage phagocytosis of tumor cells.
• Eliminating N111 glycosylation promotes CD103+ dendritic cell infiltration, increasing natural killer (NK) cell recruitment and inhibiting tumor growth.
• Combined treatment synergistically improved therapeutic efficacy in the HCC model.
• Human HCC specimens showed a positive correlation between FUT8 levels and CD47 expression, and negative correlation with CD103+ DC and NK cell infiltration.

Conclusions:

• The FUT8-SMURF1-CD47 axis is a key mechanism for CD47 upregulation in tumor cells, contributing to immune escape.
• Targeting core fucosylation of CD47 presents a promising therapeutic strategy to enhance anti-tumor immune responses.
• Inhibition of FUT8-mediated glycosylation can reprogram the tumor microenvironment to favor immune cell-mediated tumor rejection.