Combined treatment with epigenetic agents enhances anti-tumor activity of T cells by upregulating the ACRBP expression in hepatocellular carcinoma.

Objective: To evaluate the efficacy of combined epigenetic drugs of decitabine (DAC), valproic acid (VPA) and trichostatin A (TSA) on immunotherapy with a murine model of hepatocellular carcinoma (HCC).

Methods: Dendritic cells (DCs) transduced with recombinant lentivirus expressing a cancer-testis antigen, acrosin binding protein (ACRBP), are referred to as DC/ACRBP. CD8 T cells were harvested from spleens of C57BL/6 mice and activated by DC/ACRBP. Cytotoxicity of DC/ACRBP-activated T cells was analyzed by cytotoxicity and murine xenograft assays.

Results: Cytotoxicity assay results revealed that DC/ACRBP-activated T cells exhibited the highest cytotoxicity against HCC cells pre-treated with triple drugs (DAC+VPA+TSA) compared with dual drugs (DAC+VPA and DAC+TSA) and single drug (DAC, VPA and TSA) respectively. Analyses of RT-PCR and immunoblotting demonstrated that the highest ACRBP expression of HCC cells was induced by the triple drugs compared with the single and dual drugs. These results indicated that DC/ACRBP-activated T cells might be ACRBP-specific lymphocytes, and the augmented cytotoxicity may be dependent on the upregulation of ACRBP expression. These assumptions were further confirmed by xenograft tumor assay. Tumor cells of mice administrated with the triple drugs exhibited increased ACRBP expression compared with those of mice without administration. As expected, DC/ACRBP-activated T cells adopted by mice injected with the triple drugs, compared with those adopted by mice without injection, remarkably impeded growth and facilitated apoptosis of tumor cells.

Conclusion: These data suggested that combined treatment with DAC, VPA and TSA may enhance the anti-tumor efficacy of ACRBP-specific T cells by upregulating ACRBP expression in HCC.