In:
Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 78, No. 4 ( 2023-10), p. 1064-1078
Abstract:
HCC is a malignant disease. Compared with tyrosine kinase inhibitors (the classical therapy), immune checkpoint inhibitors are more effective in the treatment of HCC, despite their limited efficacy. Among these restricted factors, exhaustion of tumor-infiltrated lymphocytes, especially CD8 + T cells, is a core event. We aimed to determine the key factors contributing to CD8 + T-cell infiltration in HCC and investigate the underlying mechanisms. Approach and Results: Using machine learning and multiplex immunohistochemistry analysis, we showed that dedicator of cytokinesis protein 2 (DOCK2) was a potential indicator of infiltrated CD8 + T cells in HCC. Using RNA sequencing, flow cytometry analysis, and mouse HCC models, we demonstrated that DOCK2 inactivation accounted for infiltrated CD8 + T-cell exhaustion in tumors. Using quasi-targeted metabolomics, mass spectrum, and mass cytometry by time of flight analysis, we found that cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells suppressed DOCK2 enzymatic activity of T cells. Through virtual screening, molecular docking simulation, and experiments validation, we demonstrated that tolazamide reversed DOCK2 inactivation-mediated CD8 + T-cell exhaustion and enhanced anti–programmed death-ligand 1 antibody+apatinib immunotherapeutic effects on HCC. Conclusions: This study indicates that DOCK2 controls CD8 + T-cell infiltration in HCC, and cholesterol sulfate synthesized by sulfotransferase 2B1 in tumor cells promotes effector T-cell exhaustion. The findings suggest that the usage of conventional drugs affects immunotherapy efficacy in HCC patients.
Type of Medium:
Online Resource
ISSN:
0270-9139
DOI:
10.1097/HEP.0000000000000025
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2023
detail.hit.zdb_id:
1472120-X
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