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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
  • 194 Downloads

Abstract

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.

Keywords

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

Abbreviations

FDA

Food and Drug Administration

HCC

Hepatocellular carcinoma

HDACi

Histone deacetylase inhibitors

PTCL

Peripheral T cell lymphoma

Notes

Acknowledgements

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.

Funding

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)

References

  1. 1.
    Llopiz D, Ruiz M, Villanueva L, Iglesias T, Lasarte JJ, Pivette P, Trochon-Joseph V, Vasseur B, Dixon G, Sangro B, Sarobe P (2018) The HDAC inhibitor belinostat enhances the anti-tumor efficacy of immune checkpoint inhibitors in a murine hepatocellular carcinoma model. J Hepatol 68:S677 (abstract SAT-159) CrossRefGoogle Scholar
  2. 2.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108CrossRefGoogle Scholar
  3. 3.
    Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, Gores G (2016) Hepatocellular carcinoma. Nat Rev Dis Primers 2:16018CrossRefGoogle Scholar
  4. 4.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefGoogle Scholar
  5. 5.
    Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G (2017) Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389:56–66CrossRefGoogle Scholar
  6. 6.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefGoogle Scholar
  7. 7.
    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526CrossRefGoogle Scholar
  8. 8.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465CrossRefGoogle Scholar
  9. 9.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2014) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330CrossRefGoogle Scholar
  10. 10.
    Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, Riezu-Boj JI, Larrea E, Alfaro C, Sarobe P, Lasarte JJ, Perez-Gracia JL, Melero I, Prieto J (2013) A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 59:81–88CrossRefGoogle Scholar
  11. 11.
    El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling THR, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389:2492–2502CrossRefGoogle Scholar
  12. 12.
    Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, Davis JL, Hughes MS, Heller T, ElGindi M, Uppala A, Korangy F, Kleiner DE, Figg WD, Venzon D, Steinberg SM, Venkatesan AM, Krishnasamy V, Abi-Jaoudeh N, Levy E, Wood BJ, Greten TF (2017) Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 66:545–551CrossRefGoogle Scholar
  13. 13.
    Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33:1889–1894CrossRefGoogle Scholar
  14. 14.
    Greten TF, Sangro B (2018) Targets for immunotherapy of liver cancer. J Hepatol 68:157–166CrossRefGoogle Scholar
  15. 15.
    Jones PA, Issa JP, Baylin S (2016) Targeting the cancer epigenome for therapy. Nat Rev Genet 17:630–641CrossRefGoogle Scholar
  16. 16.
    Khan AN, Gregorie CJ, Tomasi TB (2008) Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol Immunother 57:647–654CrossRefGoogle Scholar
  17. 17.
    Saleh MH, Wang L, Goldberg MS (2016) Improving cancer immunotherapy with DNA methyltransferase inhibitors. Cancer Immunol Immunother 65:787–796CrossRefGoogle Scholar
  18. 18.
    Dubovsky JA, Powers JJ, Gao Y, Mariusso LF, Sotomayor EM, Pinilla-Ibarz JA (2011) Epigenetic repolarization of T lymphocytes from chronic lymphocytic leukemia patients using 5-aza-2′-deoxycytidine. Leuk Res 35:1193–1199CrossRefGoogle Scholar
  19. 19.
    Zhu S, Denman CJ, Cobanoglu ZS, Kiany S, Lau CC, Gottschalk SM, Hughes DP, Kleinerman ES, Lee DA (2015) The narrow-spectrum HDAC inhibitor entinostat enhances NKG2D expression without NK cell toxicity, leading to enhanced recognition of cancer cells. Pharm Res 32:779–792CrossRefGoogle Scholar
  20. 20.
    Costantini B, Kordasti SY, Kulasekararaj AG, Jiang J, Seidl T, Abellan PP, Mohamedali A, Thomas NS, Farzaneh F, Mufti GJ (2013) The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome. Haematologica 98:1196–1205CrossRefGoogle Scholar
  21. 21.
    Mikyskova R, Indrova M, Vlkova V, Bieblova J, Simova J, Parackova Z, Pajtasz-Piasecka E, Rossowska J, Reinis M (2014) DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment. J Leukoc Biol 95:743–753CrossRefGoogle Scholar
  22. 22.
    Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S (2014) Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 111:11774–11779CrossRefGoogle Scholar
  23. 23.
    Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, Makarov V, Budhu S, Slamon DJ, Wolchok JD, Pardoll DM, Beckmann MW, Zahnow CA, Merghoub T, Chan TA, Baylin SB, Strick R (2015) Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162:974–986CrossRefGoogle Scholar
  24. 24.
    Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J (2015) HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 3:1375–1385CrossRefGoogle Scholar
  25. 25.
    Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241CrossRefGoogle Scholar
  26. 26.
    Ramalingam SS, Belani CP, Ruel C, Frankel P, Gitlitz B, Koczywas M, Espinoza-Delgado I, Gandara D (2009) Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. J Thorac Oncol 4:97–101CrossRefGoogle Scholar
  27. 27.
    Mackay HJ, Hirte H, Colgan T, Covens A, MacAlpine K, Grenci P, Wang L, Mason J, Pham PA, Tsao MS, Pan J, Zwiebel J, Oza AM (2010) Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours. Eur J Cancer 46:1573–1579CrossRefGoogle Scholar
  28. 28.
    Foss F, Advani R, Duvic M, Hymes KB, Intragumtornchai T, Lekhakula A, Shpilberg O, Lerner A, Belt RJ, Jacobsen ED, Laurent G, Ben-Yehuda D, Beylot-Barry M, Hillen U, Knoblauch P, Bhat G, Chawla S, Allen LF, Pohlman B (2015) A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol 168:811–819CrossRefGoogle Scholar
  29. 29.
    O’Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, Hess G, Jurczak W, Knoblauch P, Chawla S, Bhat G, Choi MR, Walewski J, Savage K, Foss F, Allen LF, Shustov A (2015) Belinostat in patients with relapsed or refractory peripheral T-Cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol 33:2492–2499CrossRefGoogle Scholar
  30. 30.
    Ma BB, Sung F, Tao Q, Poon FF, Lui VW, Yeo W, Chan SL, Chan AT (2010) The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines. Invest New Drugs 28:107–114CrossRefGoogle Scholar
  31. 31.
    Spratlin JL, Pitts TM, Kulikowski GN, Morelli MP, Tentler JJ, Serkova NJ, Eckhardt SG (2011) Synergistic activity of histone deacetylase and proteasome inhibition against pancreatic and hepatocellular cancer cell lines. Anticancer Res 31:1093–1103PubMedPubMedCentralGoogle Scholar
  32. 32.
    Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, Picus J, Boyer M, Mo FK, Koh J, Rha SY, Hui EP, Jeung HC, Roh JK, Yu SC, To KF, Tao Q, Ma BB, Chan AW, Tong JH, Erlichman C, Chan AT, Goh BC (2012) Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol 30:3361–3367CrossRefGoogle Scholar
  33. 33.
    Gonzalez-Carmona MA, Lukacs-Kornek V, Timmerman A, Shabani S, Kornek M, Vogt A, Yildiz Y, Sievers E, Schmidt-Wolf IG, Caselmann WH, Sauerbruch T, Schmitz V (2008) CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo. Hepatology 48:157–168CrossRefGoogle Scholar
  34. 34.
    Llopiz D, Aranda F, Díaz-Valdés N, Ruiz M, Infante S, Belsúe V, Lasarte JJ, Sarobe P (2015) Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of interleukin-10 blockade in therapeutic vaccination. Oncoimmunology 5:e1075113CrossRefGoogle Scholar
  35. 35.
    Barcena-Varela M, Caruso S, Llerena S, Alvarez-Sola G, Uriarte I, Latasa MU, Urtasun R, Rebouissou S, Alvarez L, Jimenez M, Santamaria E, Rodriguez-Ortigosa C, Mazza G, Rombouts K, Jose-Eneriz ES, Rabal O, Agirre X, Iraburu M, Santos-Laso A, Banales JM, Zucman-Rossi J, Prosper F, Oyarzabal J, Berasain C, Avila MA, Fernandez-Barrena MG (2018) Dual targeting of histone methyltransferase G9a and DNA-methyltransferase 1 for the treatment of experimental hepatocellular carcinoma. Hepatology.  https://doi.org/10.1002/hep.30168 CrossRefPubMedGoogle Scholar
  36. 36.
    Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C, Yao J, Jin L, Wang H, Yang Y, Fu YX, Wang FS (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–2339CrossRefGoogle Scholar
  37. 37.
    Zhou J, Ding T, Pan W, Zhu LY, Li L, Zheng L (2009) Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer 125:1640–1648CrossRefGoogle Scholar
  38. 38.
    Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, Peppelenbosch MP, Kwekkeboom J, Verheij J, Janssen HL, Sprengers D (2013) Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology 57:183–194CrossRefGoogle Scholar
  39. 39.
    Gehring AJ, Ho ZZ, Tan AT, Aung MO, Lee KH, Tan KC, Lim SG, Bertoletti A (2009) Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 137:682–690CrossRefGoogle Scholar
  40. 40.
    Ahn E, Araki K, Hashimoto M, Li W, Riley JL, Cheung J, Sharpe AH, Freeman GJ, Irving BA, Ahmed R (2018) Role of PD-1 during effector CD8 T cell differentiation. Proc Natl Acad Sci USA 115:4749–4754PubMedGoogle Scholar
  41. 41.
    Fuertes Marraco SA, Neubert NJ, Verdeil G, Speiser DE (2015) Inhibitory receptors beyond T cell exhaustion. Front Immunol 6:310CrossRefGoogle Scholar
  42. 42.
    Steele NL, Plumb JA, Vidal L, Tjornelund J, Knoblauch P, Buhl-Jensen P, Molife R, Brown R, de Bono JS, Evans TR (2011) Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101). Cancer Chemother Pharmacol 67:1273–1279CrossRefGoogle Scholar
  43. 43.
    Dunn J, Rao S (2017) Epigenetics and immunotherapy: the current state of play. Mol Immunol 87:227–239CrossRefGoogle Scholar
  44. 44.
    Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA, Ziv E, Culhane AC, Paull EO, Sivakumar IKA, Gentles AJ, Malhotra R, Farshidfar F, Colaprico A, Parker JS, Mose LE, Vo NS, Liu J, Liu Y, Rader J, Dhankani V, Reynolds SM, Bowlby R, Califano A, Cherniack AD, Anastassiou D, Bedognetti D, Rao A, Chen K, Krasnitz A, Hu H, Malta TM, Noushmehr H, Pedamallu CS, Bullman S, Ojesina AI, Lamb A, Zhou W, Shen H, Choueiri TK, Weinstein JN, Guinney J, Saltz J, Holt RA, Rabkin CE, Lazar AJ, Serody JS, Demicco EG, Disis ML, Vincent BG, Shmulevich L (2018) The immune landscape of cancer. Immunity 48:812–830 e814CrossRefGoogle Scholar
  45. 45.
    Schmitz V, Tirado-Ledo L, Tiemann K, Raskopf E, Heinicke T, Ziske C, Gonzalez-Carmona MA, Rabe C, Wernert N, Prieto J, Qian C, Sauerbruch T, Caselmann WH (2004) Establishment of an orthotopic tumour model for hepatocellular carcinoma and non-invasive in vivo tumour imaging by high resolution ultrasound in mice. J Hepatol 40:787–791CrossRefGoogle Scholar
  46. 46.
    Robertson RT, Gutierrez PM, Baratta JL, Thordarson K, Braslow J, Haynes SM, Longmuir KJ (2016) Development, differentiation, and vascular components of subcutaneous and intrahepatic Hepa129 tumors in a mouse model of hepatocellular carcinoma. Histol Histopathol 31:403–413PubMedGoogle Scholar
  47. 47.
    Raskopf E, Dzienisowicz C, Hilbert T, Rabe C, Leifeld L, Wernert N, Sauerbruch T, Prieto J, Qian C, Caselmann WH, Schmitz V (2005) Effective angiostatic treatment in a murine metastatic and orthotopic hepatoma model. Hepatology 41:1233–1240CrossRefGoogle Scholar
  48. 48.
    Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, Li B, Turka LA, Olson EN, Greene MI, Wells AD, Hancock WW (2007) Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13:1299–1307CrossRefGoogle Scholar
  49. 49.
    Akimova T, Ge G, Golovina T, Mikheeva T, Wang L, Riley JL, Hancock WW (2010) Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs. Clin Immunol 136:348–363CrossRefGoogle Scholar
  50. 50.
    Nencioni A, Beck J, Werth D, Grunebach F, Patrone F, Ballestrero A, Brossart P (2007) Histone deacetylase inhibitors affect dendritic cell differentiation and immunogenicity. Clin Cancer Res 13:3933–3941CrossRefGoogle Scholar
  51. 51.
    Cabanel M, Brand C, Oliveira-Nunes MC, Cabral-Piccin MP, Lopes MF, Brito JM, de Oliveira FL, El-Cheikh MC, Carneiro K (2015) Epigenetic control of macrophage shape transition towards an atypical elongated phenotype by histone deacetylase activity. PLoS One 10:e0132984CrossRefGoogle Scholar
  52. 52.
    Zheng H, Zhao W, Yan C, Watson CC, Massengill M, Xie M, Massengill C, Noyes DR, Martinez GV, Afzal R, Chen Z, Ren X, Antonia SJ, Haura EB, Ruffell B, Beg AA (2016) HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin Cancer Res 22:4119–4132CrossRefGoogle Scholar
  53. 53.
    Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA 107:4275–4280CrossRefGoogle Scholar
  54. 54.
    Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–377CrossRefGoogle Scholar
  55. 55.
    Saha D, Martuza RL, Rabkin SD (2017) Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell 32:253–267 e255CrossRefGoogle Scholar
  56. 56.
    Yarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377:2500–2501CrossRefGoogle Scholar
  57. 57.
    Palomero T, Couronne L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, Carpenter Z, Abate F, Allegretta M, Haydu JE, Jiang X, Lossos IS, Nicolas C, Balbin M, Bastard C, Bhagat G, Piris MA, Campo E, Bernard OA, Rabadan R, Ferrando AA (2014) Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 46:166–170CrossRefGoogle Scholar
  58. 58.
    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, van Buuren MM, van ‘t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR (2013) Signatures of mutational processes in human cancer. Nature 500:415–421CrossRefGoogle Scholar

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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