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

  • Diana Llopiz
  • Marta Ruiz
  • Lorea Villanueva
  • Tamara Iglesias
  • Leyre Silva
  • Josune Egea
  • Juan J. Lasarte
  • Perrine Pivette
  • Véronique Trochon-Joseph
  • Bérangère Vasseur
  • Graham Dixon
  • Bruno Sangro
  • Pablo SarobeEmail author
Original Article


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.


Checkpoint inhibitors HDAC inhibitor Hepatocellular carcinoma M1 macrophages PD-1/PD-L1 expression T regulatory cells 



Food and Drug Administration


Hepatocellular carcinoma


Histone deacetylase inhibitors


Peripheral T cell lymphoma



Authors thank Dr. Gonzalez-Carmona for tumor Hepa129 tumor cell line and Dr. M. Hommel for manuscript revision.

Author contributions

DL designed and performed experiments, acquired, analyzed and interpreted the data, and revised the manuscript. MR, LV, LS, JE and TI performed experiments and revised the manuscript. JJL, PP, VT-J, BV, GD and BS participated in the design of experiments, interpretation of the data, and revised the manuscript. PS designed experiments, analyzed and interpreted the data, and wrote the manuscript. All authors read and approved the final manuscript.


This work is funded by a commercial research Grant from Onxeo. Pablo Sarobe is supported by Grants from Ministerio de Economia y Competitividad/Instituto de Salud Carlos III co-financed by European FEDER funds (PI14/00343; PI17/00249), from Fundación Bancaria La Caixa “Hepacare” project and received financial support from the “Murchante contra el cáncer” initiative. Bruno Sangro is supported by the European Commission’s 7th Framework Programme (EC FP7) Project: “Cancer Vaccine Development for Hepatocellular Carcinoma—HEPAVAC” (Grant no. 602893), by European Commission H2020, Project “Immunology and Immunotherapy of cancer: strengthening the translational aspect—HepaMUT” (Grant no. AC16/00165) and by Plan Estatal de I+D+I 2013–2016, co-financed by Instituto de Salud Carlos III—Subdirección General de Evaluación y Fomento de la investigación and Fondo Europeo de Desarrollo Regional (FEDER) (Grant no. PI16/01845).

Compliance with ethical standards

Conflict of interest

Perrine Pivette, Véronique Trochon-Joseph, Bérangère Vasseur and Graham Dixon were or are employed by Onxeo. Bruno Sangro received consulting and/or lecture fees from Adaptimmune, Astra Zeneca, Bayer Healthcare, Bristol-Myers-Squibb, Medimmune and Onxeo. All other authors declare that they have no conflict of interest.

Ethical approval

All animal procedures were approved by the Animal Ethics Committee of the Universidad de Navarra (Project approval number: E1-16(149-14E2)). They were in accordance with the ethical standards and guidelines for laboratory animals of the Universidad de Navarra.

Animal source

All mice were obtained from Envigo (Barcelona, Spain).

Cell line authentication

Hepa129 HCC cells were a kind gift from Dr. M. Gonzalez-Carmona (Bonn, Germany). Re-authentication of cells has not been performed since receipt.

Supplementary material

262_2018_2283_MOESM1_ESM.pdf (113 kb)
Supplementary material 1 (PDF 112 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Center for Applied Medical Research (CIMA), Program of Immunology and ImmunotherapyUniversity of NavarraPamplonaSpain
  2. 2.IdiSNA, Instituto de Investigación Sanitaria de NavarraPamplonaSpain
  3. 3.OnxeoParisFrance
  4. 4.Liver UnitClínica Universidad de Navarra-and CIBEREHDPamplonaSpain
  5. 5.Neem Biotech LtdAbertilleryUK

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