Overcoming immune suppression with epigenetic modification in ovarian cancer

  • Tyler R. McCaw
    Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama
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  • Troy D. Randall
    Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama
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  • Rebecca C. Arend
    Reprint requests: Rebecca C. Arend, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, 176F Room 1025, 619 19th St South, Birmingham, AL 35294-0024.
    Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, Alabama
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      The impressive successes of immunotherapy have yet to be reliably translated to treatment of ovarian cancer, which may be a consequence of the unique barriers to T cell migration and tumor engagement in the peritoneal cavity and omentum. Epigenetic alterations contribute to establishment of these barriers and other mechanisms of immune subversion; therefore, epigenetic modifying agents represent an opportunity to mount effective antitumor immune responses by disrupting this finely tuned tumor epigenetic framework. Here, we discuss how epigenetic modifiers might permit and stimulate de novo antitumor immune responses in ovarian cancer, focusing largely on 2 common classes, DNA methyltransferase and histone deacetylase inhibitors. Specifically, increasing T and NK cell trafficking to the tumor microenvironment as well as induction of altered tumor cell phenotypes that promote immune engagement and cytotoxicity may provide a platform upon which to elaborate existing immunotherapeutic strategies. Indeed, promising combination of epigenetic modifying agents with checkpoint blockade antibodies or cellular therapies in preclinical models has led to a burgeoning number of clinical trials. Therefore, rather than implementation as a monotherapy, epigenetic modifiers may well be best suited as adjuvants in combinatorial strategies, potentiating antitumor immune responses and unleashing the promise of immunotherapy in ovarian cancer.


      OVCA (ovarian cancer), Treg (regulatory T cell), MDSC (myeloid derived suppressor cell), DNMT (DNA methyltransferase), HDAC (histone deacetylase inhibitor), AZA (5-azacytidine), IFN (interferon), ENT (entinostat), GIV (givinostat), DAC (decitabine), TME (tumor microenvironment), MHC (major histocompatibility complex), CTA (cancer testis antigen), GUA (guadecitabine), DC (dendritic cell), DR4 (death receptor 4), CIITA (class II transcriptional activator), ERV (endogenous retrovirus), ISRE (interferon-stimulated response elements)
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        • Karbach J
        • Gnjatic S
        • Bender A
        • et al.
        Tumor-reactive CD8+ T-cell responses after vaccination with NY-ESO-1 peptide, CpG 7909 and Montanide ISA-51: association with survival.
        Int J Cancer. 2010; 126: 909-918
        • Odunsi K
        • Matsuzaki J
        • Karbach J
        • et al.
        Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients.
        Pro Natl Acad Sci USA. 2012; 109: 5797-5802
        • Sabbatini P
        • Tsuji T
        • Ferran L
        • et al.
        Phase I trial of overlapping long peptides from a tumor self-antigen and poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients.
        Clin Cancer Res. 2012; 18: 6497-6508
        • Topalian SL
        • Drake CG
        • Pardoll DM
        Immune checkpoint blockade: a common denominator approach to cancer therapy.
        Cancer Cell. 2015; 27: 450-461
        • Reade CJ
        • Mcvey RM
        • Tone AA
        • et al.
        The fallopian tube as the origin of high grade serous ovarian cancer: review of a paradigm shift.
        JObstet Gynaecol Can. 2014; 36: 133-140
        • Landen Jr, CN
        • Birrer MJ
        • Sood AK
        Early events in the pathogenesis of epithelial ovarian cancer.
        J Clin Oncol. 2008; 26: 995-1005
        • Nieman KM
        • Kenny HA
        • Penicka CV
        • et al.
        Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.
        Nat Med. 2011; 17: 1498
        • Wagner M
        • Dudley AC
        A three-party alliance in solid tumors: adipocytes, macrophages and vascular endothelial cells.
        Adipocyte. 2013; 2: 67-73
        • Okabe Y
        • Medzhitov R
        Tissue-specific signals control reversible program of localization and functional polarization of macrophages.
        Cell. 2014; 157: 832-844
        • Jeffery LE
        • Burke F
        • Mura M
        • et al.
        1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit t cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and foxP3.
        J Immunol. 2009; 183: 5458-5467
        • Meza-Perez S
        • Randall TD
        Immunological functions of the omentum.
        Trends Immunol. 2017; 38: 526-536
        • Bast Jr, RC
        • Hennessy B
        • Mills GB
        The biology of ovarian cancer: new opportunities for translation.
        Nat Rev Cancer. 2009; 9: 415
        • Berdasco M
        • Esteller M
        Aberrant epigenetic landscape in cancer: how cellular identity goes awry.
        Dev Cell. 2010; 19: 698-711
        • Zeller C
        • Dai W
        • Steele NL
        • et al.
        Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling.
        Oncogene. 2012; 31: 4567
      1. Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotech 2010;28:1069.

        • Choudhary C
        • Kumar C
        • Gnad F
        • et al.
        Lysine acetylation targets protein complexes and co-regulates major cellular functions.
        Science. 2009; 325: 834-840
        • Joyce JA
        • Fearon DT
        T cell exclusion, immune privilege, and the tumor microenvironment.
        Science. 2015; 348: 74-80
        • Giannakakis A
        • Karapetsas A
        • Dangaj D
        • et al.
        Overexpression of SMARCE1 is associated with CD8+ T-cell infiltration in early stage ovarian cancer.
        Int J Biochem Cell Biol. 2014; 53: 389-398
        • Wang L
        • Amoozgar Z
        • Huang J
        • et al.
        Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model.
        Cancer Immunol Res. 2015; 3: 1030-1041
        • Li H
        • Chiappinelli KB
        • Guzzetta AA
        • et al.
        Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers.
        Oncotarget. 2014; 5: 587-598
        • Connolly RM
        • Rudek MA
        • Piekarz R
        Entinostat: a promising treatment option for patients with advanced breast cancer.
        Future Oncol. 2017; 13: 1137-1148
        • Leoni F
        • Fossati G
        • Lewis EC
        • et al.
        The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo.
        Mol Med. 2005; 11: 1-15
        • Stone ML
        • Chiappinelli KB
        • Li H
        • et al.
        Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden.
        Proc NATL Acad Sci USA. 2017;
        • Peng D
        • Kryczek I
        • Nagarsheth N
        • et al.
        Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.
        Nature. 2015; 527: 249-253
        • Zhao E
        • Maj T
        • Kryczek I
        • et al.
        Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction.
        Nat Immunol. 2016; 17: 95-103
        • Italiano A
        • Soria J-C
        • Toulmonde M
        • et 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 1 study.
        Lancet Oncol. 2018; 19: 649-659
        • McCaw TR
        • Randall TD
        • Forero A
        • Buchsbaum DJ
        Modulation of antitumor immunity with histone deacetylase inhibitors.
        Immunotherapy. 2017; 9: 1359-1372
        • Hwang W-T
        • Adams SF
        • Tahirovic E
        • Hagemann IS
        • Coukos G
        Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis.
        Gynecol Oncol. 2012; 124: 192-198
        • Campoli M
        • Ferrone S
        HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance.
        Oncogene. 2008; 27: 5869
        • Akers SN
        • Odunsi K
        • Karpf AR
        Regulation of cancer germline antigen gene expression: implications for cancer immunotherapy.
        Future Oncol. 2010; 6: 717-732
        • James SR
        • Cedeno CD
        • Sharma A
        • et al.
        DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11.
        Epigenetics. 2013; 8: 849-863
        • Menendez L
        • Walker D
        • Matyunina LV
        • et al.
        Identification of candidate methylation-responsive genes in ovarian cancer.
        Mol Cancer. 2007; 6: 10
        • Adair SJ
        • Hogan KT
        Treatment of ovarian cancer cell lines with 5-aza-2′-deoxycytidine upregulates the expression of cancer-testis antigens and class I major histocompatibility complex-encoded molecules.
        Cancer Immunol Immuno. 2009; 58: 589-601
        • Siebenkäs C
        • Chiappinelli KB
        • Guzzetta AA
        • et al.
        Inhibiting DNA methylation activates cancer testis antigens and expression of the antigen processing and presentation machinery in colon and ovarian cancer cells.
        PloS One. 2017; 12e0179501
        • Woloszynska-Read A
        • Mhawech-Fauceglia P
        • Yu J
        • Odunsi K
        • Karpf AR
        Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer.
        Clin Cancer Res. 2008; 14:: 3283-3290
        • Zhang W
        • Barger CJ
        • Link PA
        • et al.
        DNA hypomethylation-mediated activation of Cancer/Testis Antigen 45 (CT45) genes is associated with disease progression and reduced survival in epithelial ovarian cancer.
        Epigenetics. 2015; 10: 736-748
        • Link PA
        • Zhang W
        • Odunsi K
        • Karpf AR
        BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer.
        Cancer Immun. 2013; 13
        • Bhalla KN
        Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies.
        JClin Oncol. 2005; 23: 3971-3993
        • Srivastava P
        • Paluch BE
        • Matsuzaki J
        • et al.
        Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts.
        Epigenetics. 2015; 10: 237-246
        • Chiappinelli KB
        • Strissel PL
        • Desrichard A
        • et al.
        Inhibiting DNA Methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses.
        Cell. 2015; 162: 974-986
        • Parker BS
        • Rautela J
        • Hertzog PJ
        Antitumour actions of interferons: implications for cancer therapy.
        Nat Rev Cancer. 2016; 16: 131
        • Hervas-Stubbs S
        • Perez-Gracia JL
        • Rouzaut A
        • et al.
        Direct effects of type I interferons on cells of the immune system.
        Clin Cancer Res. 2011; 17: 2619-2627
        • Bacher N
        • Raker V
        • Hofmann C
        • et al.
        Interferon-α suppresses cAMP to disarm human regulatory t cells.
        Cancer Res. 2013; 73: 5647-5656
        • Honda K
        • Sakaguchi S
        • Nakajima C
        • et al.
        Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection.
        Proc NTL Acad Sci USA. 2003; 100: 10872-10877
        • Schiavoni G
        • Mattei F
        • Gabriele L
        Type I Interferons as stimulators of DC-mediated cross-priming: impact on anti-tumor response.
        Front Immunol. 2013; 4: 483
        • Horak P
        • Pils D
        • Haller G
        • et al.
        Contribution of epigenetic silencing of tumor necrosis factor–related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer.
        Mol Cancer Res. 2005; 3: 335-343
        • Kayagaki N
        • Yamaguchi N
        • Nakayama M
        • Eto H
        • Okumura K
        • Yagita H
        Type I interferons (IFNs) regulate tumor necrosis factor–related apoptosis-inducing ligand (trail) expression on human T cells: a novel mechanism for the antitumor effects of  Type I IFNs.
        J Exp Med. 1999; 189: 1451-1460
        • Thomas WD
        • Hersey P
        TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells.
        J Immunol. 1998; 161: 2195-2200
        • Mony JT
        • Zhang L
        • Ma T
        • et al.
        Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model.
        Cancer Immunol Immuno. 2015; 64: 1095-1108
        • Cacan E
        Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells.
        Cell Biol Int. 2017; 41: 328-339
        • Cacan E
        Histone deacetylase-1-mediated suppression of FAS in chemoresistant ovarian cancer cells.
        Anticancer Res. 2016; 36: 2819-2826
        • Matsuzaki J
        • Tsuji T
        • Luescher IF
        • et al.
        Direct tumor recognition by a human CD4(+) T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses.
        Sci Rep. 2015; 5: 14896
        • McCaw TR
        • Li M
        • Starenki D
        • et al.
        The expression of class II major histocompatibility molecules on breast tumors delays T cell exhaustion, expands the T cell repertoire and slows tumor growth.
        bioRxiv. 2018;
        • Turner TB
        • Meza-Perez S
        • Londoño A
        • et al.
        Epigenetic modifiers upregulate MHC II and impede ovarian cancer tumor growth.
        Oncotarget. 2017; 8: 44159-44170
        • Ayers M
        • Lunceford J
        • Nebozhyn M
        • et al.
        IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade.
        J Clin Invest. 2017; 127: 2930-2940
        • Pitt JM
        • Vetizou M
        • Daillere R
        • et al.
        Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors.
        Immunity. 2016; 44: 1255-1269
        • Odunsi K
        • Matsuzaki J
        • James SR
        • et al.
        Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer.
        Cancer Immunol Res. 2014; 2: 37-49
        • Balkwill F
        • Montfort A
        • Capasso M
        B regulatory cells in cancer.
        Trends Immunol. 2013; 34169173
        • Zhang Y
        • Mei Q
        • Liu Y
        • et al.
        The safety, efficacy, and treatment outcomes of a combination of low-dose decitabine treatment in patients with recurrent ovarian cancer.
        Oncoimmunology. 2017; 6e1323619
        • Wang HF
        • Ning F
        • Liu ZC
        • et al.
        Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro.
        Cancer immunol, Immuno. 2017; 66: 355-366
        • Shen L
        • Ciesielski M
        • Ramakrishnan S
        • et al.
        Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models.
        PloS One. 2012; 7: e30815