SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment.

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) treatment faces challenges with limited immune checkpoint inhibitor efficacy.
• Tumor-infiltrated lymphocyte exhaustion, particularly CD8+ T cells, is a key factor limiting immunotherapy effectiveness in HCC.

Purpose of the Study:

• To identify key factors regulating CD8+ T-cell infiltration in HCC.
• To elucidate the mechanisms underlying CD8+ T-cell exhaustion in HCC.
• To explore therapeutic strategies targeting T-cell exhaustion for enhanced HCC immunotherapy.

Main Methods:

• Machine learning and multiplex immunohistochemistry for identifying potential biomarkers.
• RNA sequencing, flow cytometry, and mouse models to investigate DOCK2 function.
• Metabolomics, mass spectrometry, and mass cytometry to analyze molecular interactions.
• Virtual screening, molecular docking, and experimental validation to assess drug efficacy.

Main Results:

• Dedicator of cytokinesis protein 2 (DOCK2) identified as a potential indicator of CD8+ T-cell infiltration in HCC.
• DOCK2 inactivation was found to cause CD8+ T-cell exhaustion in HCC tumors.
• Cholesterol sulfate, synthesized by sulfotransferase 2B1, suppresses DOCK2 activity in T cells.
• Tolazamide demonstrated potential to reverse DOCK2 inactivation-mediated T-cell exhaustion and enhance immunotherapy.

Conclusions:

• DOCK2 plays a critical role in regulating CD8+ T-cell infiltration and function in HCC.
• Tumor-derived cholesterol sulfate contributes to effector T-cell exhaustion, impacting immunotherapy.
• Conventional drug usage may influence HCC immunotherapy outcomes, suggesting potential combination strategies.