EZH2 Inhibition: A Promising Strategy to Prevent Cancer Immune Editing

References

• Vaddepally RK , KharelP , PandeyRet al. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN Guidelines with the level of evidence. Cancers (Basel)12(3), 738–756 (2020).
   PubMed Web of Science ®Google Scholar
• O’Donnell JS , TengMWL , SmythMJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol.16(3), 151–167 (2019).
   PubMed Web of Science ®Google Scholar
• Sharma P , Hu-LieskovanS , WargoJAet al. Primary, adaptive and acquired resistance to cancer immunotherapy. Cell168(4), 707–723 (2017).
   PubMed Web of Science ®Google Scholar
• Dunn GP , OldLJ , SchreiberRD. The three Es of cancer immunoediting. Annu. Rev. Immunol.22, 329–360 (2004).
   PubMed Web of Science ®Google Scholar
• Schreiber RD , OldLJ , SmythMJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science331(6024), 1565–1570 (2011).
   PubMed Web of Science ®Google Scholar
• Deans C , MaggertKA. What do you mean, “epigenetic”. Genetics199(4), 887–896 (2015).
   PubMed Web of Science ®Google Scholar
• Burr ML , SparbierCE , ChanKLet al. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell36(4), 385–401.e8 (2019).
   PubMed Web of Science ®Google Scholar
• Toyokawa G , TakadaK , TagawaTet al. A positive correlation between the EZH2 and PD-L1 expression in resected lung adenocarcinomas. Ann. Thorac. Surg.107(2), 393–400 (2019).
   PubMed Web of Science ®Google Scholar
• Wang D , QuirosJ , MahuronKet al. Targeting EZH2 reprograms intratumoral regulatory T cells to enhance cancer immunity. Cell Rep.23(11), 3262–3274 (2018).
   PubMed Web of Science ®Google Scholar
• Xia L , ZhuX , ZhangL , XuY , ChenG , LuoJ. EZH2 enhances expression of CCL5 to promote recruitment of macrophages and invasion in lung cancer. Biotechnol. Appl. Biochem.https://doi.org/10.1002/bab.1875(2019).
   Web of Science ®Google Scholar
• Burnet FM . The concept of immunological surveillance. Prog. Exp. Tumor Res.13, 1–27 (1970).
   PubMed Web of Science ®Google Scholar
• Thomas L . On immunosurveillance in human cancer. Yale J. Biol. Med.55(3–4), 329–333 (1982).
   PubMed Web of Science ®Google Scholar
• Appay V , DouekDC , PriceDA. CD8+ T cell efficacy in vaccination and disease. Nat. Med.14(6), 623–628 (2008).
   PubMed Web of Science ®Google Scholar
• Malmberg KJ , CarlstenM , BjörklundAet al. Natural killer cell-mediated immunosurveillance of human cancer. Semin. Immunol.31, 20–29 (2017).
   PubMed Web of Science ®Google Scholar
• Iannello A , ThompsonTW , ArdolinoMet al. Immunosurveillance and immunotherapy of tumors by innate immune cells. Curr. Opin. Immunol.38, 52–58 (2016).
   PubMed Web of Science ®Google Scholar
• Hayday AC . γδ T cell update: adaptate orchestrators of immune surveillance. J. Immunol.203(2), 311–320 (2019).
   PubMed Web of Science ®Google Scholar
• Melssen M , SlingluffCL. Vaccines targeting helper T cells for cancer immunotherapy. Curr. Opin. Immunol.47, 85–92 (2017).
   PubMed Web of Science ®Google Scholar
• Pardoll DM , TopalianSL. The role of CD4+ T cell responses in antitumor immunity. Curr. Opin. Immunol.10(5), 588–594 (1998).
   PubMed Web of Science ®Google Scholar
• Pawelec G . Tumour escape: antitumour effectors too much of a good thing. Cancer Immunol. Immunother.53(3), 262–274 (2004).
   PubMed Web of Science ®Google Scholar
• Vinay DS , RyanEP , PawelecGet al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin. Cancer Biol.35(Suppl.), S185–S198 (2015).
   PubMed Web of Science ®Google Scholar
• McGranahan N , SwantonC. Cancer evolution constrained by the immune microenvironment. Cell170(5), 825–827 (2017).
   PubMed Web of Science ®Google Scholar
• Haq R . Trapping cancers as they adapt to survive. Cancer Discov.7(11), 1216–1217 (2017).
   PubMed Web of Science ®Google Scholar
• Rosenthal R , CadieuxEL , SalgadoRet al. Neoantigen-directed immune escape in lung cancer evolution. Nature567(7749), 479–485 (2019).
   PubMed Web of Science ®Google Scholar
• Palucka AK , CoussensLM. The basis of oncoimmunology. Cell164(6), 1233–1247 (2016).
   PubMed Web of Science ®Google Scholar
• Choi SY , GoutPW , CollinsCCet al. Epithelial immune cell-like transition (EIT): a proposed transdifferentiation process underlying immune-suppressive activity of epithelial cancers. Differentiation83(5), 293–298 (2012).
   PubMed Web of Science ®Google Scholar
• Dunn GP , BruceAT , IkedaHet al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol.3(11), 991–998 (2002).
   PubMed Web of Science ®Google Scholar
• Beatty GL , GladneyWL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res.21(4), 687–692 (2015).
   PubMed Web of Science ®Google Scholar
• Talukdar S , BhoopathiP , EmdadLet al. Dormancy and cancer stem cells: an enigma for cancer therapeutic targeting. Adv. Cancer Res.141, 43–84 (2019).
   PubMed Web of Science ®Google Scholar
• Garrido F , AptsiauriN , DoorduijnEMet al. The urgent need to recover MHC class I in cancers for effective immunotherapy. Curr. Opin. Immunol.39, 44–51 (2016).
   PubMed Web of Science ®Google Scholar
• Han LY , FletcherMS , UrbauerDLet al. HLA class I antigen processing machinery component expression and intratumoral T-Cell infiltrate as independent prognostic markers in ovarian carcinoma. Clin. Cancer Res.14(11), 3372–3379 (2008).
   PubMed Web of Science ®Google Scholar
• Bukur J , JasinskiS , SeligerB. The role of classical and non-classical HLA class I antigens in human tumors. Semin. Cancer Biol.22(4), 350–358 (2012).
   PubMed Web of Science ®Google Scholar
• Adrián Cabestré F , MoreauP , RiteauBet al. HLA-G expression in human melanoma cells: protection from NK cytolysis. J. Reprod. Immunol.43(2), 183–193 (1999).
   PubMed Web of Science ®Google Scholar
• Seliger B , Jasinski-BergnerS , QuandtDet al. HLA-E expression and its clinical relevance in human renal cell carcinoma. Oncotarget7(41), 67360–67372 (2016).
   PubMedGoogle Scholar
• Pardoll DM . The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer12(4), 252–264 (2012).
   PubMed Web of Science ®Google Scholar
• Schlößer HA , TheurichS , Shimabukuro-VornhagenAet al. Overcoming tumor-mediated immunosuppression. Immunotherapy6(9), 973–988 (2014).
   PubMed Web of Science ®Google Scholar
• Anderson AC , JollerN , KuchrooVK. Lag-3, Tim-3 and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity44(5), 989–1004 (2016).
   PubMed Web of Science ®Google Scholar
• Marin-Acevedo JA , DholariaB , SoyanoAEet al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J. Hematol. Oncol.11(1), 39 (2018).
   PubMed Web of Science ®Google Scholar
• Schnell A , BodL , MadiAet al. The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity. Cell Res.30, 285–299 (2020).
   PubMed Web of Science ®Google Scholar
• Burkholder B , HuangRY , BurgessRet al. Tumor-induced perturbations of cytokines and immune cell networks. Biochim. Biophys. Acta1845(2), 182–201 (2014).
   PubMed Web of Science ®Google Scholar
• Prendergast GC , MalachowskiWP , DuHadawayJBet al. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res.77(24), 6795–6811 (2017).
   PubMed Web of Science ®Google Scholar
• Choi SY , CollinsCC , GoutPWet al. Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite. J. Pathol.230(4), 350–355 (2013).
   PubMed Web of Science ®Google Scholar
• Morrot A , da FonsecaLM , SalustianoEJet al. Metabolic symbiosis and immunomodulation: how tumor cell-derived lactate may disturb innate and adaptive immune responses. Front Oncol8, 81 (2018).
   PubMed Web of Science ®Google Scholar
• Binnewies M , RobertsEW , KerstenKet al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med.24(5), 541–550 (2018).
   PubMed Web of Science ®Google Scholar
• Guo C , ManjiliMH , SubjeckJRet al. Therapeutic cancer vaccines: past, present and future. Adv. Cancer Res.119, 421–475 (2013).
   PubMed Web of Science ®Google Scholar
• Hinrichs CS , RosenbergSA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol. Rev.257(1), 56–71 (2014).
   PubMed Web of Science ®Google Scholar
• Scott AM , WolchokJD , OldLJ. Antibody therapy of cancer. Nat. Rev. Cancer12(4), 278–287 (2012).
   PubMed Web of Science ®Google Scholar
• Gallotta M , AssiH , DegagnéÉet al. Inhaled TLR9 agonist renders lung tumors permissive to PD-1 blockade by promoting optimal CD4. Cancer Res.78(17), 4943–4956 (2018).
   PubMed Web of Science ®Google Scholar
• Kauffman EC , LiuH , SchwartzMJet al. Toll-like receptor 7 agonist therapy with imidazoquinoline enhances cancer cell death and increases lymphocytic infiltration and proinflammatory cytokine production in established tumors of a renal cell carcinoma mouse model. J. Oncol.2012, 103298 (2012).
   PubMedGoogle Scholar
• Wu X , LiJ , ConnollyEMet al. Combined anti-VEGF and Anti-CTLA-4 therapy elicits humoral immunity to galectin-1 which is associated with favorable clinical outcomes. Cancer Immunol. Res.5(6), 446–454 (2017).
   PubMed Web of Science ®Google Scholar
• Kujawski M , ZhangC , HerrmannAet al. Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. Cancer Res.70(23), 9599–9610 (2010).
   PubMed Web of Science ®Google Scholar
• Lu C , TalukderA , SavageNMet al. JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer. Oncoimmunology6(3), e1291106 (2017).
   PubMed Web of Science ®Google Scholar
• Luke JJ , BaoR , SweisRFet al. WNT/β-catenin pathway activation correlates with immune exclusion across human cancers. Clin. Cancer Res.25(10), 3074–3083 (2019).
   PubMed Web of Science ®Google Scholar
• Yang H , LeeWS , KongSJet al. STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade. J. Clin. Invest.130, 4350–4364 (2019).
   Google Scholar
• Anderson KG , StromnesIM , GreenbergPD. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell31(3), 311–325 (2017).
   PubMed Web of Science ®Google Scholar
• Bonifazi M , RossiM , MojaLet al. Bevacizumab in clinical practice: prescribing appropriateness relative to national indications and safety. Oncologist17(1), 117–124 (2012).
   PubMed Web of Science ®Google Scholar
• Anwar MA , ShahM , KimJet al. Recent clinical trends in Toll-like receptor targeting therapeutics. Med. Res. Rev.39(3), 1053–1090 (2019).
   PubMed Web of Science ®Google Scholar
• Zou W , WolchokJD , ChenL. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers and combinations. Sci. Transl. Med.8(328), 328rv4 (2016).
   PubMed Web of Science ®Google Scholar
• Seidel JA , OtsukaA , KabashimaK. Anti-PD-1 and Anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy and limitations. Front. Oncol.8, 86 (2018).
   PubMed Web of Science ®Google Scholar
• Harjunpää H , GuillereyC. TIGIT as an emerging immune checkpoint. Clin. Exp. Immunol.200(2), 108–119 (2019).
   PubMed Web of Science ®Google Scholar
• Friedlaender A , AddeoA , BannaG. New emerging targets in cancer immunotherapy: the role of TIM3. ESMO Open4(Suppl. 3), e000497 (2019).
   PubMedGoogle Scholar
• Long L , ZhangX , ChenFet al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer9(5–6), 176–189 (2018).
   PubMedGoogle Scholar
• Sheng S , ZhangJ , AiJet al. Aberrant expression of IL-23/IL-23R in patients with breast cancer and its clinical significance. Mol. Med. Rep.17(3), 4639–4644 (2018).
   PubMed Web of Science ®Google Scholar
• Baird AM , LeonardJ , NaickerKMet al. IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small-cell lung cancer. Lung Cancer79(1), 83–90 (2013).
   PubMed Web of Science ®Google Scholar
• Soares KC , RuckiAA , KimVet al. TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. Oncotarget6(40), 43005–43015 (2015).
   PubMedGoogle Scholar
• Terabe M , RobertsonFC , ClarkKet al. Blockade of only TGF-β 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy. Oncoimmunology6(5), e1308616 (2017).
   PubMed Web of Science ®Google Scholar
• de Gramont A , FaivreS , RaymondE. Novel TGF-β inhibitors ready for prime time in onco-immunology. Oncoimmunology6(1), e1257453 (2017).
   PubMed Web of Science ®Google Scholar
• Morse MA , HobeikaAC , OsadaTet al. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood112(3), 610–618 (2008).
   PubMed Web of Science ®Google Scholar
• Ohue Y , NishikawaH. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target. Cancer Sci110(7), 2080–2089 (2019).
   PubMed Web of Science ®Google Scholar
• Miret JJ , KirschmeierP , KoyamaSet al. Suppression of myeloid cell arginase activity leads to therapeutic response in a NSCLC mouse model by activating anti-tumor immunity. J. Immunother. Cancer7(1), 32 (2019).
   PubMedGoogle Scholar
• Fleming V , HuX , WeberRet al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front. Immunol.9, 398 (2018).
   PubMed Web of Science ®Google Scholar
• Myers KV , AmendSR , PientaKJ. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. Mol. Cancer18(1), 94 (2019).
   PubMedGoogle Scholar
• Poh AR , ErnstM. Targeting macrophages in cancer: from bench to bedside. Front. Oncol.8, 49 (2018).
   PubMed Web of Science ®Google Scholar
• WARBURG O . On respiratory impairment in cancer cells. Science124(3215), 269–270 (1956).
   PubMed Web of Science ®Google Scholar
• Feron O . Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother. Oncol.92(3), 329–333 (2009).
   PubMed Web of Science ®Google Scholar
• Marchiq I , PouysségurJ. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H(+) symporters. J. Mol. Med. (Berl)94(2), 155–171 (2016).
   PubMed Web of Science ®Google Scholar
• Kouidhi S , BenAyed F , ElgaaiedBenammar A. Targeting tumor metabolism: a new challenge to improve immunotherapy. Front. Immunol.9, 353 (2018).
   PubMed Web of Science ®Google Scholar
• Choi SYC , EttingerSL , LinDet al. Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer. Cancer Med.7(7), 3385–3392 (2018).
   PubMed Web of Science ®Google Scholar
• Todenhöfer T , SeilerR , StewartCet al. Selective inhibition of the lactate transporter MCT4 reduces growth of invasive bladder cancer. Mol. Cancer Ther.17(12), 2746–2755 (2018).
   PubMed Web of Science ®Google Scholar
• Polański R , HodgkinsonCL , FusiAet al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin. Cancer Res.20(4), 926–937 (2014).
   PubMed Web of Science ®Google Scholar
• Romero-Garcia S , Moreno-AltamiranoMM , Prado-GarciaHet al. Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front. Immunol.7, 52 (2016).
   PubMed Web of Science ®Google Scholar
• Jackson CM , ChoiJ , LimM. Mechanisms of immunotherapy resistance: lessons from glioblastoma. Nat. Immunol.20(9), 1100–1109 (2019).
   PubMed Web of Science ®Google Scholar
• Hodi FS , O’DaySJ , McDermottDFet al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med.363(8), 711–723 (2010).
   PubMed Web of Science ®Google Scholar
• Wolchok JD , Chiarion-SileniV , GonzalezRet al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med.377(14), 1345–1356 (2017).
   PubMed Web of Science ®Google Scholar
• Luke JJ , FlahertyKT , RibasAet al. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat. Rev. Clin. Oncol.14(8), 463–482 (2017).
   PubMed Web of Science ®Google Scholar
• Rizvi NA , HellmannMD , SnyderAet al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small-cell lung cancer. Science348(6230), 124–128 (2015).
   PubMed Web of Science ®Google Scholar
• Snyder A , MakarovV , MerghoubTet al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med.371(23), 2189–2199 (2014).
   PubMed Web of Science ®Google Scholar
• Hugo W , ZaretskyJM , SunLet al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell165(1), 35–44 (2016).
   PubMed Web of Science ®Google Scholar
• Anagnostou V , SmithKN , FordePMet al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small-cell lung cancer. Cancer Discov.7(3), 264–276 (2017).
   PubMed Web of Science ®Google Scholar
• Gettinger S , ChoiJ , HastingsKet al. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov.7(12), 1420–1435 (2017).
   PubMed Web of Science ®Google Scholar
• Peng D , KryczekI , NagarshethNet al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature527(7577), 249–253 (2015).
   PubMed Web of Science ®Google Scholar
• Cristescu R , MoggR , AyersMet al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science362(6411), eaar3593 (2018).
   PubMed Web of Science ®Google Scholar
• Koyama S , AkbayEA , LiYYet al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun.7, 10501 (2016).
   PubMed Web of Science ®Google Scholar
• Chapuy B , StewartC , DunfordAJet al. Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. Blood134(26), 2369–2382 (2019).
   PubMed Web of Science ®Google Scholar
• Baylin SB , OhmJE. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction. Nat. Rev. Cancer6(2), 107–116 (2006).
   PubMed Web of Science ®Google Scholar
• Morales V , Richard-FoyH. Role of histone N-terminal tails and their acetylation in nucleosome dynamics. Mol. Cell Biol.20(19), 7230–7237 (2000).
   PubMed Web of Science ®Google Scholar
• Portela A , EstellerM. Epigenetic modifications and human disease. Nat. Biotechnol.28(10), 1057–1068 (2010).
   PubMed Web of Science ®Google Scholar
• Kanwal R , GuptaS. Epigenetic modifications in cancer. Clin. Genet.81(4), 303–311 (2012).
   PubMed Web of Science ®Google Scholar
• Qamra A , XingM , PadmanabhanNet al. Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma. Cancer Discov.7(6), 630–651 (2017).
   PubMed Web of Science ®Google Scholar
• Wierzbinska JA , TothR , IshaqueNet al. Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL. Genome Med.12(1), 29 (2020).
   PubMed Web of Science ®Google Scholar
• Berglund A , MillsM , PutneyRMet al. Methylation of immune synapse genes modulates tumor immunogenicity. J. Clin. Invest.130(2), 974–980 (2020).
   PubMed Web of Science ®Google Scholar
• Wylie B , CheeJ , ForbesCAet al. Acquired resistance during adoptive cell therapy by transcriptional silencing of immunogenic antigens. Oncoimmunology8, 1609874 (2019).
   PubMed Web of Science ®Google Scholar
• Liu J , HeD , ChengLet al. p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer. Oncogene39(19), 3939–3951 (2020).
   PubMed Web of Science ®Google Scholar
• Floess S , FreyerJ , SiewertCet al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol.5(2), e38 (2007).
   PubMed Web of Science ®Google Scholar
• Lu Z , ZouJ , LiSet al. Epigenetic therapy inhibits metastases by disrupting premetastatic niches. Nature579(7798), 284–290 (2020).
   PubMed Web of Science ®Google Scholar
• Mitra S , LaussM , CabritaRet al. Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma. Mol. Oncol.14(5), 933–950 (2020).
   PubMed Web of Science ®Google Scholar
• Topper MJ , VazM , MarroneKAet al. The emerging role of epigenetic therapeutics in immuno-oncology. Nat. Rev. Clin. Oncol.17(2), 75–90 (2020).
   PubMed Web of Science ®Google Scholar
• Chiappinelli KB , ZahnowCA , AhujaNet al. Combining epigenetic and immunotherapy to combat cancer. Cancer Res.76(7), 1683–1689 (2016).
   PubMed Web of Science ®Google Scholar
• Kelly AD , IssaJJ. The promise of epigenetic therapy: reprogramming the cancer epigenome. Curr. Opin. Genet. Dev.42, 68–77 (2017).
   PubMed Web of Science ®Google Scholar
• Símová J , PollákováV , IndrováMet al. Immunotherapy augments the effect of 5-azacytidine on HPV16-associated tumours with different MHC class I-expression status. Br. J. Cancer105(10), 1533–1541 (2011).
   PubMed Web of Science ®Google Scholar
• Christmas BJ , RafieCI , HopkinsACet al. Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol. Res.6(12), 1561–1577 (2018).
   PubMed Web of Science ®Google Scholar
• Park J , ThomasS , MunsterPN. Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy. Epigenomics7(4), 641–652 (2015).
   PubMed Web of Science ®Google Scholar
• Juergens RA , WrangleJ , VendettiFPet al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small-cell lung cancer. Cancer Discov.1(7), 598–607 (2011).
   PubMed Web of Science ®Google Scholar
• Crea F , ClermontPL , MaiAet al. Histone modifications, stem cells and prostate cancer. Curr. Pharm. Des.20(11), 1687–1697 (2014).
   PubMed Web of Science ®Google Scholar
• Völkel P , BaryA , RabyLet al. Ezh1 arises from Ezh2 gene duplication but its function is not required for zebrafish development. Sci. Rep.9(1), 4319 (2019).
   PubMedGoogle Scholar
• Wang Q , LiuL , ZhangSet al. Long noncoding RNA NEAT1 suppresses hepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter region and promotion of H3K27me3 methylation. Exp. Mol. Med.52(3), 461–472 (2020).
   PubMed Web of Science ®Google Scholar
• Curry E , GreenI , Chapman-RotheNet al. Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells. Clin. Epigenetics7, 84 (2015).
   PubMed Web of Science ®Google Scholar
• Coward WR , Feghali-BostwickCA , JenkinsGet al. A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis. FASEB J.28(7), 3183–3196 (2014).
   PubMed Web of Science ®Google Scholar
• Kim E , KimM , WooDHet al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell23(6), 839–852 (2013).
   PubMed Web of Science ®Google Scholar
• Lawrence CL , BaldwinAS. Non-canonical EZH2 transcriptionally activates RelB in triple negative breast cancer. PLoS ONE11(10), e0165005 (2016).
   PubMed Web of Science ®Google Scholar
• Jones A , WangH. Polycomb repressive complex 2 in embryonic stem cells: an overview. Protein Cell1(12), 1056–1062 (2010).
   PubMed Web of Science ®Google Scholar
• Nutt SL , KeenanC , ChopinMet al. EZH2 function in immune cell development. Biol. Chem.401(8), 933–943 (2020).
   PubMed Web of Science ®Google Scholar
• Deevy O , BrackenAP. PRC2 functions in development and congenital disorders. Development146(19), dev181354 (2019).
   PubMed Web of Science ®Google Scholar
• Cyrus S , BurkardtD , WeaverDDet al. PRC2-complex related dysfunction in overgrowth syndromes: a review of EZH2, EED and SUZ12 and their syndromic phenotypes. Am. J. Med. Genet. C Semin. Med. Genet.181(4), 519–531 (2019).
   PubMed Web of Science ®Google Scholar
• Matsubara T , ToyokawaG , TakadaKet al. The association and prognostic impact of enhancer of zeste homologue 2 expression and epithelial-mesenchymal transition in resected lung adenocarcinoma. PLoS ONE14(5), e0215103 (2019).
   PubMed Web of Science ®Google Scholar
• Wu X , ScottH , CarlssonSVet al. Increased EZH2 expression in prostate cancer is associated with metastatic recurrence following external beam radiotherapy. Prostate79(10), 1079–1089 (2019).
   PubMed Web of Science ®Google Scholar
• Stazi G , TaglieriL , NicolaiAet al. Dissecting the role of novel EZH2 inhibitors in primary glioblastoma cell cultures: effects on proliferation, epithelial-mesenchymal transition, migration and on the pro-inflammatory phenotype. Clin. Epigenetics11(1), 173 (2019).
   PubMed Web of Science ®Google Scholar
• Avan A , CreaF , PaolicchiEet al. Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells. Mol. Cancer Ther.11(8), 1735–1746 (2012).
   PubMed Web of Science ®Google Scholar
• Huang B , HuangM , LiQ. Cancer-associated fibroblasts promote angiogenesis of hepatocellular carcinoma by VEGF-mediated EZH2/VASH1 pathway. Technol. Cancer Res. Treat18, (2019). https://doi.org/10.1177/1533033819879905
   Web of Science ®Google Scholar
• Zeng Z , YangY , WuH. MicroRNA-765 alleviates the malignant progression of breast cancer via interacting with EZH1. Am. J. Transl. Res.11(7), 4500–4507 (2019).
   PubMed Web of Science ®Google Scholar
• Nakagawa M , KitabayashiI. Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies. Cancer Sci.109(8), 2342–2348 (2018).
   PubMed Web of Science ®Google Scholar
• Quintanal-Villalonga Á , ChanJM , YuHAet al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol.17(6), 360–371 (2020).
   PubMed Web of Science ®Google Scholar
• Clermont PL , LinD , CreaFet al. Polycomb-mediated silencing in neuroendocrine prostate cancer. Clin. Epigenetics7, 40 (2015).
   PubMed Web of Science ®Google Scholar
• Zhao Y , WangXX , WuWet al. EZH2 regulates PD-L1 expression via HIF-1α in non-small-cell lung cancer cells. Biochem. Biophys. Res. Commun.517(2), 201–209 (2019).
   PubMed Web of Science ®Google Scholar
• Xiao G , JinLL , LiuCQet al. EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma. J. Immunother. Cancer7(1), 300 (2019).
   PubMed Web of Science ®Google Scholar
• Wu J , LanierLL. Natural killer cells and cancer. Adv. Cancer Res.90, 127–156 (2003).
   PubMed Web of Science ®Google Scholar
• Bugide S , GreenMR , WajapeyeeN. Inhibition of enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells. Proc. Natl Acad. Sci. USA115(15), E3509–E3518 (2018).
   PubMed Web of Science ®Google Scholar
• Yin J , LeavenworthJW , LiYet al. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc. Natl Acad. Sci. USA112(52), 15988–15993 (2015).
   PubMed Web of Science ®Google Scholar
• Yin Y , QiuS , LiXet al. EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment. J. Neuroinflammation14(1), 220 (2017).
   PubMedGoogle Scholar
• Pang B , ZhengXR , TianJXet al. EZH2 promotes metabolic reprogramming in glioblastomas through epigenetic repression of EAF2-HIF1α signaling. Oncotarget7(29), 45134–45143 (2016).
   PubMedGoogle Scholar
• Bray M , DriscollJ , HugginsJW. Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-L-homocysteine hydrolase inhibitor. Antiviral Res.45(2), 135–147 (2000).
   PubMed Web of Science ®Google Scholar
• Miranda TB , CortezCC , YooCBet al. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol. Cancer Ther.8(6), 1579–1588 (2009).
   PubMed Web of Science ®Google Scholar
• Tan J , YangX , ZhuangLet al. Pharmacologic disruption of polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev.21(9), 1050–1063 (2007).
   PubMed Web of Science ®Google Scholar
• Crea F , HurtEM , MathewsLAet al. Pharmacologic disruption of polycomb repressive complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol. Cancer10, 40 (2011).
   PubMed Web of Science ®Google Scholar
• Hung SW , ModyH , MarracheSet al. Pharmacological reversal of histone methylation presensitizes pancreatic cancer cells to nucleoside drugs: in vitro optimization and novel nanoparticle delivery studies. PLoS ONE8, e71196 (2013).
   PubMed Web of Science ®Google Scholar
• Hoy SM . Tazemetostat: first approval. Drugs80(5), 513–521 (2020).
   PubMed Web of Science ®Google Scholar
• Knutson SK , WarholicNM , WigleTJet al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl Acad. Sci. USA110(19), 7922–7927 (2013).
   PubMed Web of Science ®Google Scholar
• Knutson SK , WarholicNM , WigleTJet al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl Acad Sci. USA110(19), 7922–7927 (2013).
   PubMed Web of Science ®Google Scholar
• Knutson SK , KawanoS , MinoshimaYet al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol. Cancer Ther.13(4), 842–854 (2014).
   PubMed Web of Science ®Google Scholar
• Italiano A , SoriaJC , ToulmondeMet al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, Phase I study. Lancet Oncol.19(5), 649–659 (2018).
   PubMed Web of Science ®Google Scholar
• Leslie M . First EZH2 inhibitor approved-for rare sarcoma. Cancer Discov.10(3), 333–334 (2020).
   PubMed Web of Science ®Google Scholar
• Sarkozy C , MorschhauserF , DuboisSet al. A LYSA Phase Ib study of tazemetostat (EPZ-6438) plus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) with poor prognosis features. Clin. Cancer Res.26(13), 3145–3153 (2020).
   PubMed Web of Science ®Google Scholar
• McCabe MT , OttHM , GanjiGet al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature492(7427), 108–112 (2012).
   PubMed Web of Science ®Google Scholar
• Yap TA , WinterJN , Giulino-RothLet al. Phase I study of the novel enhancer of zeste homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors. Clin. Cancer Res.25(24), 7331–7339 (2019).
   PubMed Web of Science ®Google Scholar
• Vaswani RG , GehlingVS , DakinLAet al. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for Phase I clinical trials for B-Cell lymphomas. J. Med. Chem.59(21), 9928–9941 (2016).
   PubMed Web of Science ®Google Scholar
• Lu B , ShenX , ZhangLet al. Discovery of EBI-2511: a highly potent and orally active EZH2 inhibitor for the treatment of non-hodgkin’s lymphoma. ACS Med. Chem. Lett.9(2), 98–102 (2018).
   PubMed Web of Science ®Google Scholar
• Huang Y , ZhangJ , YuZet al. Discovery of first-in-class, potent and orally bioavailable embryonic ectoderm development (EED) inhibitor with robust anticancer efficacy. J. Med. Chem.60(6), 2215–2226 (2017).
   PubMed Web of Science ®Google Scholar
• He Y , SelvarajuS , CurtinMLet al. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat. Chem. Biol.13(4), 389–395 (2017).
   PubMed Web of Science ®Google Scholar
• Marabondo S , KaufmanHL. High-dose interleukin-2 (IL-2) for the treatment of melanoma: safety considerations and future directions. Expert Opin. Drug Saf.16(12), 1347–1357 (2017).
   PubMed Web of Science ®Google Scholar
• Zingg D , Arenas-RamirezN , SahinDet al. The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep.20(4), 854–867 (2017).
   PubMed Web of Science ®Google Scholar
• Goswami S , ApostolouI , ZhangJet al. Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J. Clin. Invest.128(9), 3813–3818 (2018).
   PubMed Web of Science ®Google Scholar
• Hong YK , LiY , PanditHet al. Epigenetic modulation enhances immunotherapy for hepatocellular carcinoma. Cell. Immunol.336, 66–74 (2019).
   PubMed Web of Science ®Google Scholar
• Zhou L , MudiantoT , MaXet al. Targeting EZH2 enhances antigen presentation, antitumor immunity and circumvents anti-PD-1 resistance in head and neck cancer. Clin. Cancer Res.26(1), 290–300 (2020).
   PubMed Web of Science ®Google Scholar
• Momparler RL , CôtéS , MarquezVEet al. Comparison of the antineoplastic action of 3-deazaneplanocin-A and inhibitors that target the catalytic site of EZH2 histone methyltransferase. Cancer Rep. Rev.3, 1–4 (2020).
   Google Scholar
• Sun F , LiJ , YuQet al. Loading 3-deazaneplanocin A into pegylated unilamellar liposomes by forming transient phenylboronic acid-drug complex and its pharmacokinetic features in Sprague-Dawley rats. Eur. J. Pharm. Biopharm80(2), 323–331 (2012).
   PubMed Web of Science ®Google Scholar
• Chamoto K , HataeR , HonjoT. Current issues and perspectives in PD-1 blockade cancer immunotherapy. Int. J. Clin. Oncol.25(5), 790–800 (2020).
   PubMed Web of Science ®Google Scholar
• Kailayangiri S , AltvaterB , LeschSet al. EZH2 inhibition in ewing sarcoma upregulates G. Mol. Ther.27(5), 933–946 (2019).
   PubMed Web of Science ®Google Scholar
• Singh AK , McGuirkJP. CAR T cells: continuation in a revolution of immunotherapy. Lancet Oncol.21(3), e168–e178 (2020).
   PubMed Web of Science ®Google Scholar
• Bisserier M , WajapeyeeN. Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas. Blood131(19), 2125–2137 (2018).
   PubMed Web of Science ®Google Scholar
• Crea F , FornaroL , BocciGet al. EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis. Cancer Metastasis Rev.31(3–4), 753–761 (2012).
   PubMed Web of Science ®Google Scholar
• Xu Z , SunY , GuoYet al. NF-YA promotes invasion and angiogenesis by upregulating EZH2-STAT3 signaling in human melanoma cells. Oncol. Rep.35(6), 3630–3638 (2016).
   PubMed Web of Science ®Google Scholar
• Luo J , WangK , YehSet al. LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling. Nat Commun10(1), 2571 (2019).
   PubMedGoogle Scholar
• Chen Z , DuY , LiuXet al. EZH2 inhibition suppresses bladder cancer cell growth and metastasis via the JAK2/STAT3 signaling pathway. Oncol. Lett.18(1), 907–915 (2019).
   PubMed Web of Science ®Google Scholar
• Kim KH , RobertsCW. Targeting EZH2 in cancer. Nat. Med.22(2), 128–134 (2016).
   PubMed Web of Science ®Google Scholar
• Yamamoto Y , NingG , HowittBEet al. In vitro and in vivo correlates of physiological and neoplastic human Fallopian tube stem cells. J. Pathol.238(4), 519–530 (2016).
   PubMed Web of Science ®Google Scholar
• Xu B , AbourbihS , SircarKet al. Enhancer of zeste homolog 2 expression is associated with metastasis and adverse clinical outcome in clear cell renal cell carcinoma: a comparative study and review of the literature. Arch. Pathol. Lab. Med.137(10), 1326–1336 (2013).
   PubMed Web of Science ®Google Scholar
• O’Carroll D , ErhardtS , PaganiMet al. The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol.21(13), 4330–4336 (2001).
   PubMed Web of Science ®Google Scholar
• Wei L , WangJ , LampertEet al. Intratumoral and intertumoral genomic heterogeneity of multifocal localized prostate cancer impacts molecular classifications and genomic prognosticators. Eur. Urol.71(2), 183–192 (2017).
   PubMed Web of Science ®Google Scholar
• Chan TA , YarchoanM , JaffeeEet al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol.30(1), 44–56 (2019).
   PubMed Web of Science ®Google Scholar
• Fornaro L , VivaldiC , OrlandiPet al. Longitudinal evaluation of angiogenesis-related circulating biomarkers during second-line treatment with paclitaxel and ramucirumab in advanced gastroesophageal cancer. Ann. Oncol.30(Suppl. 4), iv88 (2019).
   Google Scholar
• Forschner A , BattkeF , HadaschikDet al. Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma - results of a prospective biomarker study. J. Immunother. Cancer7(1), 180 (2019).
   PubMedGoogle Scholar
• Holdenrieder S , StieberP. Apoptotic markers in cancer. Clin. Biochem.37(7), 605–617 (2004).
   PubMed Web of Science ®Google Scholar
• Holdenrieder S , NagelD , SchalhornAet al. Clinical relevance of circulating nucleosomes in cancer. Ann. NY Acad. Sci.1137, 180–189 (2008).
   PubMed Web of Science ®Google Scholar
• Gabler C , BlankN , HieronymusTet al. Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis. Ann. Rheum. Dis.63(9), 1135–1144 (2004).
   PubMed Web of Science ®Google Scholar
• Thierry AR , ElMessaoudi S , GahanPBet al. Origins, structures and functions of circulating DNA in oncology. Cancer Metastasis Rev.35(3), 347–376 (2016).
   PubMed Web of Science ®Google Scholar
• Holdenrieder S , StieberP , BodenmüllerHet al. Nucleosomes in serum as a marker for cell death. Clin. Chem. Lab. Med.39(7), 596–605 (2001).
   PubMed Web of Science ®Google Scholar
• Holdenrieder S , DharumanY , StandopJet al. Novel serum nucleosomics biomarkers for the detection of colorectal cancer. Anticancer Res.34(5), 2357–2362 (2014).
   PubMed Web of Science ®Google Scholar
• McAnena P , BrownJA , KerinMJ. Circulating nucleosomes and nucleosome modifications as biomarkers in cancer. Cancers (Basel)9(1), 5 (2017).
   PubMed Web of Science ®Google Scholar
• Bauden M , PamartD , AnsariDet al. Circulating nucleosomes as epigenetic biomarkers in pancreatic cancer. Clin. Epigenetics7, 106 (2015).
   PubMed Web of Science ®Google Scholar
• Rahier JF , DruezA , FaugerasLet al. Circulating nucleosomes as new blood-based biomarkers for detection of colorectal cancer. Clin. Epigenetics9, 53 (2017).
   PubMed Web of Science ®Google Scholar
• Guiot J , StrumanI , ChavezVet al. Altered epigenetic features in circulating nucleosomes in idiopathic pulmonary fibrosis. Clin. Epigenetics9, 84 (2017).
   PubMed Web of Science ®Google Scholar