Regulatory T Cell Inhibition by P60 Combined with Adenoviral AFP Transduced Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma

Abstract

<strong>Background & Aims:</strong> Vaccination with tumor-associated antigen-pulsed dendritic cells leads to specific T-cell response against hepato-cellular carcinoma. However, clinical response has been shown to be limited. High regulatory T-cell count is associated with poor prognosis and seems to mediate immune tolerance in hepatocellular carcinoma. Forkhead box P3-peptide inhibitor P60 has been shown to specifically inhibit regulatory T-cell function in murine models. Aim of this study was to investigate whether P60 can improve the immune response induced by vaccination with adenovirus-transduced dendritic cells expressing alpha-fetoprotein in subcutaneous and orthotopic murine models for hepatocellular carcinoma.<br /> <strong>Methods:</strong> Mice developing subcutaneous or orthotopic HCC received daily treatment with P60 starting at different tumor stages. Additionally, mice were vaccinated twice with dendritic cells expressing alpha-fetoprotein.<br /> <strong>Results:</strong> In a preventive setting prior to tumor engraftment, vaccination with alpha-fetoprotein-expressing dendritic cells significantly decreased tumor growth in a subcutaneous model (<em>p</em> = .0256), but no further effects were achieved by addition of P60. However, P60 enhanced the antitumoral effect of a vaccination with alpha-fetoprotein-expressing dendritic cells in established subcutaneous and orthotopic hepatocellular carcinoma characterized by high Treg levels (<em>p</em> = .011).<br /> <strong>Conclusion:</strong> In this study, we showed that vaccination with alpha-fetoprotein-expressing dendritic cells in combination with a specific inhibition of regulatory T-cells by using P60 leads to synergistic tumor inhibition and prolonged survival. This emphasizes the importance of regulatory T-cells inhibition for obtaining an effective antitumoral immune response in hepatocellular carcinoma.