The role of NK cells in oncolytic viral therapy: a focus on hepatocellular carcinoma

Abstract

Natural killer (NK) cells have a key role in host anti-tumour immune responses via direct killing of tumour cells and promotion of adaptive immune responses. They are therefore attractive targets to promote the anti-tumour efficacy of oncolytic viral therapies. However, NK cells are also potent components of the host anti-viral immune response, and therefore have the potential for detrimental anti-viral responses, limiting the spread and persistence of oncolytic viruses. Oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma (HCC), a leading cause of cancer-related death with a high unmet clinical need. In this review, we highlight the role of NK cells in oncolytic virus therapy, their potential for improving treatment options for patients with HCC, and discuss current and potential strategies targeting NK cells in combination with oncolytic viral therapies.

Keywords

Oncolytic virus / natural killer cell / NK cell / immunotherapy / hepatocellular carcinoma

References

[1] Vivier E,Baratin M,Ugolini S.Functions of natural killer cells. Nat Immunol 2008;9:503-10.

[2] Bastidas-Legarda LY.Conserved and variable natural killer cell receptors: diverse approaches to viral infections.Immunology2019;156:319-28 PMCID:PMC6418463

[3] Blunt MD.Activating killer cell immunoglobulin-like receptors: Detection, function and therapeutic use.Int J Immunogenet2020;47:1-12

[4] Crinier A,Ugolini S.SnapShot: natural killer cells.Cell2020;180:1280-1280.e1

[5] Vivier E,Moretta A.Innate or adaptive immunity?.Science2011;331:44-9 PMCID:PMC3089969

[6] Huntington ND,Rautela J.The cancer-natural killer cell immunity cycle.Nat Rev Cancer2020;20:437-54

[7] Cai L,Zhou L.Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients.Clin Immunol2008;129:428-37

[8] Chew V,Lee D.Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma.Gut2012;61:427-38 PMCID:PMC3273680

[9] Wu Y,Pan WD.Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions.Hepatology2013;57:1107-16

[10] Melcher A,Rooney CM.Thunder and lightning: immunotherapy and oncolytic viruses collide.Mol Ther2011;19:1008-16 PMCID:PMC3129809

[11] Cook M.Clinical application of oncolytic viruses: a systematic review.Int J Mol Sci2020;21:7505 PMCID:PMC7589713

[12] Macedo N,Haq R.Clinical landscape of oncolytic virus research in 2020.J Immunother Cancer2020;8:e001486 PMCID:PMC7552841

[13] Doniņa S,Proboka G.Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study.Melanoma Res2015;25:421-6 PMCID:PMC4560272

[14] Babiker HM,Husnain M.Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma.Oncolytic Virother2017;6:11-8 PMCID:PMC5308590

[15] Alberts P,Brokāne L.Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c patient, a small cell lung cancer stage IIIA patient, and a histiocytic sarcoma stage IV patient-three case reports.APMIS2016;124:896-904

[16] Harada JN.p53-Independent and -dependent requirements for E1B-55K in adenovirus type 5 replication.J Virol1999;73:5333-44 PMCID:PMC112589

[17] Cao GD,Sun Q.The oncolytic virus in cancer diagnosis and treatment.Front Oncol2020;10:1786 PMCID:PMC7509414

[18] Xia ZJ,Zhang L.[Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus].Ai Zheng2004;23:1666-70

[19] Ribas A,Puzanov I.Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy.Cell2017;170:1109-19.e10 PMCID:PMC8034392

[20] Chesney J,Collichio F.Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma.J Clin Oncol2018;36:1658-67 PMCID:PMC6075852

[21] Wan PK,Seymour LW.Beyond cancer cells: Targeting the tumor microenvironment with gene therapy and armed oncolytic virus.Mol Ther2021;29:1668-82 PMCID:PMC8116634

[22] Marelli G,Lemoine NR.Oncolytic viral therapy and the immune system: a double-edged sword against cancer.Front Immunol2018;9:866 PMCID:PMC5932159

[23] Breitbach CJ,Bell JC.Oncolytic viruses: therapeutics with an identity crisis.EBioMedicine2016;9:31-6 PMCID:PMC4972563

[24] Li X,Li H.The efficacy of oncolytic adenovirus is mediated by T-cell responses against virus and tumor in Syrian hamster model.Clin Cancer Res2017;23:239-49

[25] Lemos de Matos A,McFadden G.Oncolytic viruses and the immune system: the dynamic duo.Mol Ther Methods Clin Dev2020;17:349-58 PMCID:PMC7015832

[26] Ferguson MS,Wang Y.Systemic delivery of oncolytic viruses: hopes and hurdles.Adv Virol2012;2012:805629 PMCID:PMC3287020

[27] Bessis N,Boissier MC.Immune responses to gene therapy vectors: influence on vector function and effector mechanisms.Gene Ther2004;11 Suppl 1:S10-7

[28] Eto Y,Mukai Y,Nakagawa S.et al. Development of PEGylated adenovirus vector with targeting ligand.Int J Pharm2008;354:3-8

[29] Breitbach CJ,De Silva N.Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans.Cancer Res2013;73:1265-75

[30] Breitbach CJ,Lemay CG.Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow.Mol Ther2007;15:1686-93

[31] Bhat R.Emerging role of Natural killer cells in oncolytic virotherapy.Immunotargets Ther2015;4:65-77 PMCID:PMC4918259

[32] Marotel M,Hagerman A.The two-faces of NK cells in oncolytic virotherapy.Cytokine Growth Factor Rev2020;56:59-68

[33] Thorne SH,Contag CH.Synergistic antitumor effects of immune cell-viral biotherapy.Science2006;311:1780-4

[34] Filley AC.Immune system, friend or foe of oncolytic virotherapy? Front Oncol 2017;7:106. PMCID:PMC5440545

[35] Miller CG.Fraser, Requirement of an integrated immune response for successful neuroattenuated HSV-1 therapy in an intracranial metastatic melanoma model.Mol Ther2003;7:741-7

[36] Allen C,Nakamura T.Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity.Cancer Res2006;66:11840-50

[37] Heiber JF.Vesicular stomatitis virus expressing tumor suppressor p53 is a highly attenuated, potent oncolytic agent.J Virol2011;85:10440-50 PMCID:PMC3187518

[38] Jarahian M,Fournier P.Activation of natural killer cells by newcastle disease virus hemagglutinin-neuraminidase.J Virol2009;83:8108-21 PMCID:PMC2715740

[39] Ogbomo H,Lun X.Myxoma virus infection promotes NK lysis of malignant gliomas in vitro and in vivo.PLoS One2013;8:e66825 PMCID:PMC3677932

[40] Leung EYL,Kennedy PR.NK cells augment oncolytic adenovirus cytotoxicity in ovarian cancer.Mol Ther Oncolytics2020;16:289-301 PMCID:PMC7068056

[41] Rintoul JL,Tai LH.ORFV: a novel oncolytic and immune stimulating parapoxvirus therapeutic.Mol Ther2012;20:1148-57 PMCID:PMC3369287

[42] Miyamoto S,Nakamura T.Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma.Cancer Res2012;72:2609-21

[43] Samson A,Scott K.Oncolytic reovirus as a combined antiviral and anti-tumour agent for the treatment of liver cancer.Gut2018;67:562-73 PMCID:PMC5868283

[44] Böttcher JP,Chakravarty P.NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control.Cell2018;172:1022-37.e14 PMCID:PMC5847168

[45] Dighe AS,Old LJ.Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors.Immunity1994;1:447-56

[46] Zhang Q,Zheng X.Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity.Nat Immunol2018;19:723-32

[47] Tomita K,Tachibana M.Correlation between adenovirus-neutralizing antibody titer and adenovirus vector-mediated transduction efficiency following intratumoral injection.Anticancer Res2012;32:1145-52

[48] Russell SJ,Peng KW.Remission of disseminated cancer after systemic oncolytic virotherapy.Mayo Clin Proc2014;89:926-33 PMCID:PMC4225126

[49] Alvarez-Breckenridge CA,Price R.NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors.Nat Med2012;18:1827-34 PMCID:PMC3668784

[50] Alkayyal AA,Kennedy MA.NK-cell recruitment is necessary for eradication of peritoneal carcinomatosis with an IL12-expressing maraba virus cellular vaccine.Cancer Immunol Res2017;5:211-21

[51] El-Sherbiny YM,Wetherill LF.Controlled infection with a therapeutic virus defines the activation kinetics of human natural killer cells in vivo.Clin Exp Immunol2015;180:98-107 PMCID:PMC4367098

[52] Prestwich RJ,Steele LP.Reciprocal human dendritic cell-natural killer cell interactions induce antitumor activity following tumor cell infection by oncolytic reovirus.J Immunol2009;183:4312-21

[53] Kim Y,Lee TJ.Complex role of NK cells in regulation of oncolytic virus-bortezomib therapy.Proc Natl Acad Sci U S A2018;115:4927-32 PMCID:PMC5948955

[54] Chen J,Yuan S.Oncolytic adenovirus complexes coated with lipids and calcium phosphate for cancer gene therapy.ACS Nano2016;10:11548-60

[55] Jemal A,Xu J.Cancer statistics, 2010.CA Cancer J Clin2010;60:277-300

[56] El-Serag HB.Epidemiology of viral hepatitis and hepatocellular carcinoma.Gastroenterology2012;142:1264-73.e1 PMCID:PMC3338949

[57] D'Amico G,Pagliaro L.Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.J Hepatol2006;44:217-31

[58] Vogel A,Chau I.Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol2018;29:iv238-55

[59] Park JW,Colombo M.Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study.Liver Int2015;35:2155-66 PMCID:PMC4691343

[60] Younossi ZM,Henry L.Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.Hepatology2015;62:1723-30

[61] Peiseler M.Inflammatory mechanisms underlying nonalcoholic steatohepatitis and the transition to hepatocellular carcinoma.Cancers (Basel)2021;13:730 PMCID:PMC7916589

[62] El-Serag HB,Javadi F.The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.Clin Gastroenterol Hepatol2006;4:369-80

[63] Saunders D,Allison M.Systematic review: the association between obesity and hepatocellular carcinoma - epidemiological evidence.Aliment Pharmacol Ther2010;31:1051-63

[64] Cancer Genome Atlas Research Network. Electronic address: [e-mail]; Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell2017;169:1327-41.e23

[65] Sia D,Martinez-Quetglas I.Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features.Gastroenterology2017;153:812-26

[66] Pfister D,Pinyol R.NASH limits anti-tumour surveillance in immunotherapy-treated HCC.Nature2021;592:450-6 PMCID:PMC8046670

[67] Association for the Study of the Liver. Electronic address: [e-mail]; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.J Hepatol2018;69:182-236

[68] Finn RS,Ikeda M.Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med2020;382:1894-905

[69] Sangro B,Hervás-Stubbs S.Advances in immunotherapy for hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol2021;18:525-43 PMCID:PMC8042636

[70] El-Shemi AG,Na Y.Combined therapy with oncolytic adenoviruses encoding TRAIL and IL-12 genes markedly suppressed human hepatocellular carcinoma both in vitro and in an orthotopic transplanted mouse model.J Exp Clin Cancer Res2016;35:74 PMCID:PMC4859966

[71] Mondal M,He P.Recent advances of oncolytic virus in cancer therapy.Hum Vaccin Immunother2020;16:2389-402 PMCID:PMC7644205

[72] Bach P,Hoffmann C.Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus.Cancer Res2013;73:865-74

[73] Chen C,Lin Z.A bystander cell-based GM-CSF secreting vaccine synergized with a low dose of cyclophosphamide presents therapeutic immune responses against murine hepatocellular carcinoma.Cell Mol Immunol2013;10:349-59 PMCID:PMC4003209

[74] Heo J,Ruo L.Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer.Nat Med2013;19:329-36 PMCID:PMC4268543

[75] Moehler M,Lee HC.Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).Oncoimmunology2019;8:1615817 PMCID:PMC6682346

[76] Breitbach CJ,Hwang TH,Burke J.The emerging therapeutic potential of the oncolytic immunotherapeutic Pexa-Vec (JX-594).Oncolytic Virother2015;4:25-31 PMCID:PMC4918374

[77] Paglino JC.Vesicular stomatitis virus has extensive oncolytic activity against human sarcomas: rare resistance is overcome by blocking interferon pathways.J Virol2011;85:9346-58 PMCID:PMC3165768

[78] Barber GN.Vesicular stomatitis virus as an oncolytic vector.Viral Immunol2004;17:516-27

[79] Jebar AH,Vile RG,Melcher AA.Progress in clinical oncolytic virus-based therapy for hepatocellular carcinoma.J Gen Virol2015;96:1533-50

[80] Melzer MK,Altomonte J.Oncolytic vesicular stomatitis virus as a viro-immunotherapy: defeating cancer with a "Hammer" and "Anvil".Biomedicines2017;5:8 PMCID:PMC5423493

[81] Altomonte J,Schulz S.Synergistic antitumor effects of transarterial viroembolization for multifocal hepatocellular carcinoma in rats.Hepatology2008;48:1864-73

[82] Hastie E.Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer.J Gen Virol2012;93:2529-45 PMCID:PMC4091291

[83] Dix BR,Braithwaite AW.Does the antitumor adenovirus ONYX-015/dl1520 selectively target cells defective in the p53 pathway?.J Virol2001;75:5443-7 PMCID:PMC114255

[84] Makower D,Kaufman H.Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies.Clin Cancer Res2003;9:693-702

[85] He Q,Zou Q.Transarterial injection of H101 in combination with chemoembolization overcomes recurrent hepatocellular carcinoma.World J Gastroenterol2011;17:2353-5 PMCID:PMC3098405

[86] Lin XJ,Lao XM,Li SP.Transarterial injection of recombinant human type-5 adenovirus H101 in combination with transarterial chemoembolization (TACE) improves overall and progressive-free survival in unresectable hepatocellular carcinoma (HCC).BMC Cancer2015;15:707 PMCID:PMC4608280

[87] Zhang KJ,Wang SB.Targeting gene-viro-therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma.J Biomed Sci2012;19:20 PMCID:PMC3311074

[88] Cawood R,Carroll F.Use of tissue-specific microRNA to control pathology of wild-type adenovirus without attenuation of its ability to kill cancer cells.PLoS Pathog2009;5:e1000440 PMCID:PMC2678247

[89] Racanelli V.The liver as an immunological organ.Hepatology2006;43:S54-62

[90] Gentschev I,Adelfinger M.Efficient colonization and therapy of human hepatocellular carcinoma (HCC) using the oncolytic vaccinia virus strain GLV-1h68.PLoS One2011;6:e22069 PMCID:PMC3133637

[91] Lin Y,Liang J.Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers.Proc Natl Acad Sci U S A2014;111:E4504-12 PMCID:PMC4210284

[92] Zhang H,Lin Y.Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma.Sci Transl Med2017;9:eaam7996

[93] Li Z,Zhang Y,Liu Q.Efficacy and safety of oncolytic viruses in randomized controlled trials: a systematic review and meta-analysis.Cancers (Basel)2020;12:1416 PMCID:PMC7352817

[94] Becknell B.Interleukin-2, interleukin-15, and their roles in human natural killer cells.Adv Immunol2005;86:209-39

[95] Santos JM,Cervera-Carrascon V.Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity.J Immunother Cancer2020;8:e000188 PMCID:PMC7057530

[96] Antony PA.CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2.J Immunother2005;28:120-8 PMCID:PMC1242172

[97] Trinchieri G.Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.Annu Rev Immunol1995;13:251-76

[98] Ferlazzo G,Thomas D.Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs.Proc Natl Acad Sci U S A2004;101:16606-11 PMCID:PMC534504

[99] Ahmed J,Yuan M.A new oncolytic V accinia virus augments antitumor immune responses to prevent tumor recurrence and metastasis after surgery.J Immunother Cancer2020;8:e000415 PMCID:PMC7206973

[100] Rautela J.IL-15 signaling in NK cell cancer immunotherapy.Curr Opin Immunol2017;44:1-6

[101] Tosic V,Kranz DM.Myxoma virus expressing a fusion protein of interleukin-15 (IL15) and IL15 receptor alpha has enhanced antitumor activity.PLoS One2014;9:e109801 PMCID:PMC4199602

[102] Ye JF,Liu MY.The combination of NK and CD8+T cells with CCL20/IL15-armed oncolytic adenoviruses enhances the growth suppression of TERT-positive tumor cells.Cell Immunol2017;318:35-41

[103] Kowalsky SJ,Feist M.Superagonist IL-15-armed oncolytic virus elicits potent antitumor immunity and therapy that are enhanced with PD-1 blockade.Mol Ther2018;26:2476-86 PMCID:PMC6171074

[104] Backhaus PS,Hartmann L.Immunological effects and viral gene expression determine the efficacy of oncolytic measles vaccines encoding IL-12 or IL-15 agonists.Viruses2019;11:914 PMCID:PMC6832518

[105] Romee R,Berrien-Elliott MM.Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.Sci Transl Med2016;8:357ra123 PMCID:PMC5436500

[106] Zhuang L,Rettman P.Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma.Hepatol Int2019;13:75-83 PMCID:PMC6513806

[107] Choi IK,Zhang SN.Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rbeta2 or IL-18Ralpha.Gene Ther2011;18:898-909 PMCID:PMC3169807

[108] Li Q,Ren HL.Multiple effects of IL-21 on human NK cells in ex vivo expansion.Immunobiology2015;220:876-88

[109] Chen T,Liao Q.IL-21 arming potentiates the anti-tumor activity of an oncolytic vaccinia virus in monotherapy and combination therapy.J Immunother Cancer2021;9:e001647 PMCID:PMC7843316

[110] Nishio N,Liu H.Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors.Cancer Res2014;74:5195-205 PMCID:PMC4167556

[111] Stephenson KB,Davies E,Lichty BD.Expressing human interleukin-15 from oncolytic vesicular stomatitis virus improves survival in a murine metastatic colon adenocarcinoma model through the enhancement of anti-tumor immunity.Cancer Gene Ther2012;19:238-46

[112] Passaro C,De Laura I.Arming an oncolytic herpes simplex virus type 1 with a single-chain fragment variable antibody against PD-1 for experimental glioblastoma therapy.Clin Cancer Res2019;25:290-9 PMCID:PMC6800097

[113] Zhang Y,Wei M.Recombinant adenovirus expressing a soluble fusion protein PD-1/CD137L subverts the suppression of CD8⁺ T cells in HCC.Mol Ther2019;27:1906-18 PMCID:PMC6838906

[114] Tanoue K,Watanabe N.Armed oncolytic adenovirus-expressing PD-L1 mini-body enhances antitumor effects of chimeric antigen receptor T cells in solid tumors.Cancer Res2017;77:2040-51 PMCID:PMC5392365

[115] Hsu J,Marathe M.Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade.J Clin Invest2018;128:4654-68 PMCID:PMC6159991

[116] André P,Soulas C.Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells.Cell2018;175:1731-43.e13 PMCID:PMC6292840

[117] Speck T,Veinalde R.Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors.Clin Cancer Res2018;24:2128-37

[118] Gauthier L,Anceriz N.Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity.Cell2019;177:1701-13.e16

[119] Bald T,Smyth MJ.The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies.Nat Immunol2020;21:835-47

[120] Sharma R.Beyond first-line immune checkpoint inhibitor therapy in patients with hepatocellular carcinoma.Front Immunol2021;12:652007 PMCID:PMC8005707

[121] Liu Z,Kalinski P,Bartlett DL.Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy.Nat Commun2017;8:14754 PMCID:PMC5378974

[122] Zamarin D,Subudhi SK.Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy.Sci Transl Med2014;6:226ra32 PMCID:PMC4106918

[123] Marchini A,Rommelaere J.Overcoming barriers in oncolytic virotherapy with HDAC inhibitors and immune checkpoint blockade.Viruses2016;8:9 PMCID:PMC4728569

[124] Poggi A,Garuti A,Gobbi M.Effective in vivo induction of NKG2D ligands in acute myeloid leukaemias by all-trans-retinoic acid or sodium valproate.Leukemia2009;23:641-8

[125] Ruf B,Venturelli S.Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma.Mol Ther Oncolytics2015;2:15019 PMCID:PMC4782956

[126] Liu E,Banerjee P.Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors.N Engl J Med2020;382:545-53 PMCID:PMC7101242

[127] Tseng HC,Badeti S.Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma.Nat Commun2020;11:4810 PMCID:PMC7511348

[128] Chen X,Chu J.A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases.Oncotarget2016;7:27764-77 PMCID:PMC5053686

[129] Li F,Hou W.CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency.J Immunother Cancer2020;8:e000131 PMCID:PMC7057442

[130] Gao J,Zhang L.Failure recovery of circulating NKG2D⁺CD56^dim NK cells in HBV-associated hepatocellular carcinoma after hepatectomy predicts early recurrence.Oncoimmunology2015;5:e1048061 PMCID:PMC4760296

[131] Tai LH,Bélanger S.Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells.Cancer Res2013;73:97-107

[132] Park BH,Liu TC.Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial.Lancet Oncol2008;9:533-42

[133] Liu Y,Liu W.Intravenous injection of the oncolytic virus M1 awakens antitumor T cells and overcomes resistance to checkpoint blockade.Cell Death Dis2020;11:1062 PMCID:PMC7733593