Targeted Activation of JAML+ CD8+ T Cells Enhances Immunotherapy in Hepatocellular Carcinoma

Objective: Cytotoxic T lymphocytes (CTLs) are pivotal in the therapeutic approach to hepatocellular carcinoma (HCC). Recent research has shown that junctional adhesion molecule-like protein (JAML) is capable of promoting the antitumor activity of CD8+ T cells. Our research investigates the role of JAML+ CD8 T cells in HCC. Methods: We employed time-of-flight mass cytometry (CyTOF) and an orthotopic mouse model of HCC to investigate histone modifications in tumor-infiltrating immune cells undergoing immunotherapy. Flow cytometry was used to assess CD4+ T cell differentiation and the expression of JAML in CD8+ T cells infiltrating HCC. Correlation analysis demonstrated a strong positive correlation between LDHA+ CD4 T cells and JAML+ CD8 T cells. Subsequently, we evaluated the therapeutic effects of agonistic anti-JAML antibody, both in conjunction with and without immunotherapy. Finally, RNA sequencing was performed to uncover potential regulatory mechanisms. Results: Immunotherapy substantially elevated the percentage of CD8+ T cells infiltrating HCC and altered histone modifications such as H3K18la in CD4+ T cells. Flow cytometry revealed that lactate promotes the differentiation of CD4+ T cells into Th1 cells. Lactate dehydrogenase A (LDHA) converts pyruvate to lactate. Correlation analysis revealed a strong positive relationship between LDHA+ CD4+ T cells and JAML+ CD8+ T cells in patients responsive to immunotherapy. High expression of JAML in CD8+ T cells is linked to a more favorable prognosis. In vivo experiments, the agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice, independent of the benefit of αPDL1-mediated immunotherapy. Pathway enrichment analysis revealed that JAML enhances CTLs responses through the oxidative phosphorylation pathway. Conclusions: Agonizing JAML can enhance the response of CTLs in treating HCC, and this effect is independent of the benefits provided by αPDL1-mediated immunotherapy, thereby offering a more effective treatment strategy for advanced HCC.