Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2019-03, Vol.68 (3), p.379-393
• Main Authors: Llopiz, Diana, Ruiz, Marta, Villanueva, Lorea, Iglesias, Tamara, Silva, Leyre, Egea, Josune, Lasarte, Juan J., Pivette, Perrine, Trochon-Joseph, Véronique, Vasseur, Bérangère, Dixon, Graham, Sangro, Bruno, Sarobe, Pablo
• Format: Article
• Language: English
• Subjects: Animals; Antigen-presenting cells; Antitumor activity; Cancer Research; Carcinoma, Hepatocellular - drug therapy; Cell Line, Tumor; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Disease Models, Animal; Drug Therapy, Combination; Effector cells; Female; Hepatocellular carcinoma; Histone deacetylase; Histone Deacetylase Inhibitors - administration & dosage; Humans; Hydroxamic Acids - administration & dosage; Immune checkpoint inhibitors; Immunology; Immunosuppressive agents; Immunotherapy; Liver cancer; Liver Neoplasms, Experimental - drug therapy; Lymphocytes T; Macrophages - physiology; Medicine; Medicine & Public Health; Mice; Mice, Inbred C3H; Monoclonal antibodies; Oncology; Original; Original Article; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Sulfonamides - administration & dosage; T-Lymphocytes, Regulatory - immunology; Targeted cancer therapy; γ-Interferon
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-018-2283-0

Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFN-γ production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection. These results provide a rationale for testing Belinostat in combination with checkpoint inhibitors to enhance their therapeutic activity in patients with HCC.