Anti-TIM-3 Antibody Prevents Lymphocyte Apoptosis and Enhances Dendritic Cell Cancer Therapy

Currently, there is a strong unmet need for a new intervention therapy for hepatocellular carcinoma (HCC). One candidate therapy uses dendritic cells (DCs), which are professional antigen-presenting cells that are characterized by their potent ability to elicit immune responses to foreign antigens. DCs may be attractive adjuvant agents for cancer therapy but the effect of DCs therapy is restricted because of the immunosuppressive nature of the tumor microenvironment. T-cell immunoglobulin and mucin protein-3 (TIM-3) is a marker of this immunosuppressive tumor environment. Interaction of TIM-3 with its ligand, galectin 9, triggers cell death in activated T cells. In this study, we evaluated the antitumor effects of DC vaccine therapy in combination with TIM-3 blockade in a murine HCC system. In an animal cancer prevention model, BALB/c mice were immunized with DCs with or without anti-TIM-3 antibody before challenging with HCC tumor cells (BNL). In an animal cancer therapeutic model, BALB/c mice were inoculated with DCs with or without anti-TIM-3 antibody 10 days after injection with BNL cells. The mechanism of this combination therapy was investigated using immunohistologic staining of the treated tumors and flow cytometry of lymphocytes. DC and anti-TIM-3 antibody combination treatment prevented tumor development to a greater extent than DCs alone. In the therapeutic model, the outgrowth of the established tumors was significantly reduced in mice treated with the combination of DCs and anti-TIM-3 antibody. Immunohistological analyses of the therapeutic model showed marked infiltration of CD4+ cells and CD8+ T-cells in the established BNL tumors of mice treated with both DCs and anti-TIM-3 antibody. Anti-TIM-3 antibody treatment reduces lymphocyte apoptosis and enhances the antitumor effect of DC therapy in a murine HCC model