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

Abstract

Background and Aims: 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.

Characterization of lymphocyte‐rich hepatocellular carcinoma and the prognostic role of tertiary lymphoid structures

“…NCKAP1L impedes HCC proliferation by intensifying the Rb1/p53 pathway 36 . DOCK2 has been identified as a potential marker for CD8 + T cell infiltration in HCC 37 . In addition, antigen presentation by MHC class II (HLA‐DMB, HLA‐DRA, HLA‐DRB5) is activated in LR‐HCC.…”

Cancer‐associated fibroblasts contribute to the immunosuppressive landscape and influence the efficacy of the combination therapy of PD‐1 inhibitors and antiangiogenic agents in hepatocellular carcinoma

“…19 A recent study found that HCC cells with expressed SULT2B1 inhibited DOCK2 enzyme activity, allowing tumor cells to acquire immunotherapy tolerance. 41 For advanced HCC, treatments have ranged from molecularly targeted monotherapies to tumor immune monotherapies to combination therapies. 42 In our study, the CAF high cluster had a better response to sorafenib and sunitinib that inhibit angiogenesis.…”

Targets of tumor microenvironment for potential drug development

“…Wang and colleagues revealed that the exhaustion of infiltrated CD8 + T cell in tumors is related to suppressed DOCK2 enzymatic activity in T cells in hepatocellular carcinoma (HCC), which is mediated by cholesterol sulfate synthesized by sulfotransferase 2B1 (SULT2B1) in tumor cells. They identified that CD8 + T‐cell exhaustion mediated by DOCK2 inactivation can be reversed by tolazamide 125 . As an RNA‐binding protein that regulates neuronal RNA stability and translation, fragile X mental retardation protein (FMRP), is highly expressed in human cancers and may function in antitumor immunity.…”