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Improving cancer immunotherapy with DNA methyltransferase inhibitors

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity.

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Abbreviations

AML:

Acute myeloid leukemia

AZA:

Azacitidine

CLL:

Chronic lymphocytic leukemia

CTA:

Cancer testis antigen

CTL:

Cytotoxic T lymphocyte

DAC:

Decitabine

DNMT:

DNA methyltransferases

DNMTi:

DNA methyltransferase inhibitor

HDAC:

Histone deacetylase

MAGE:

Melanoma-associated antigen

MDS:

Myelodysplastic syndrome

MDSC:

Myeloid-derived suppressor cell

MHC I:

Major histocompatibility complex class I

NK cells:

Natural killer cells

NKG2D:

Natural-killer group 2, member D

NSCLC:

Non-small cell lung cancer

KIR:

Killer immunoglobulin-like receptor

Tregs:

Regulatory T cells

References

  1. Hanahan D, Weinberg R (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  2. Baylin S, Jones P (2011) A decade of exploring the cancer epigenome: biological and translational implications. Nat Rev Cancer 11:726–734. doi:10.1038/nrc3130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159. doi:10.1056/nejmra072067

    Article  CAS  PubMed  Google Scholar 

  4. Rodríguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med. doi:10.1038/nm.2305

    PubMed  Google Scholar 

  5. Dawson M, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150:12–27. doi:10.1016/j.cell.2012.06.013

    Article  CAS  PubMed  Google Scholar 

  6. Minucci S, Pelicci P (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51. doi:10.1038/nrc1779

    Article  CAS  PubMed  Google Scholar 

  7. West A, Johnstone R (2014) New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 124:30–39. doi:10.1172/jci69738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xu W, Parmigiani R, Marks P (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26:5541–5552. doi:10.1038/sj.onc.1210620

    Article  CAS  PubMed  Google Scholar 

  9. Choudhary C, Kumar C, Gnad F, Nielsen M, Rehman M, Walther T, Olsen J, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840. doi:10.1126/science.1175371

    Article  CAS  PubMed  Google Scholar 

  10. Stresemann C, Lyko F (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 123:8–13. doi:10.1002/ijc.23607

    Article  CAS  PubMed  Google Scholar 

  11. Derissen E, Beijnen J, Schellens J (2013) Concise drug review: azacitidine and decitabine. Oncologist 18:619–624. doi:10.1634/theoncologist.2012-0465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bubeník J (2004) MHC class I down-regulation: tumour escape from immune surveillance? (Review). Int J Oncol 25:487–491. doi:10.3892/ijo.25.2.487

    PubMed  Google Scholar 

  13. Tomasi T, Magner W, Khan A (2006) Epigenetic regulation of immune escape genes in cancer. Cancer Immunol Immun 55:1159–1184. doi:10.1007/s00262-006-0164-4

    Article  Google Scholar 

  14. Maio M, Coral S, Fratta E, Altomonte M, Sigalotti L (2003) Epigenetic targets for immune intervention in human malignancies. Oncogene 22:6484–6488. doi:10.1038/sj.onc.1206956

    Article  CAS  PubMed  Google Scholar 

  15. Fratta E, Coral S, Covre A, Parisi G, Colizzi F, Danielli R, Marie Nicolay H, Sigalotti L, Maio M (2011) The biology of cancer testis antigens: putative function, regulation and therapeutic potential. Mol Oncol 5:164–182. doi:10.1016/j.molonc.2011.02.001

    Article  CAS  PubMed  Google Scholar 

  16. Dubovsky J, McNeel D, Powers J, Gordon J, Sotomayor E, Pinilla-Ibarz J (2009) Treatment of chronic lymphocytic leukemia with a hypomethylating agent induces expression of NXF2, an immunogenic cancer testis antigen. Clin Cancer Res 15:3406–3415. doi:10.1158/1078-0432.ccr-08-2099

    Article  CAS  PubMed  Google Scholar 

  17. Atanackovic D, Luetkens T, Kloth B, Fuchs G, Cao Y, Hildebrandt Y et al (2011) Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia. Am J Hematol 86:918–922. doi:10.1002/ajh.22141

    Article  CAS  PubMed  Google Scholar 

  18. Cruz C, Gerdemann U, Leen A, Shafer J, Ku S, Tzou B, Horton T et al (2011) Improving T-cell therapy for relapsed EBV-negative Hodgkin lymphoma by targeting upregulated MAGE-A4. Clin Cancer Res 17:7058–7066. doi:10.1158/1078-0432.ccr-11-1873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fonsatti E, Nicolay H, Sigalotti L, Calabro L, Pezzani L, Colizzi F et al (2007) Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2′-deoxycytidine in cutaneous melanoma: immunotherapeutic implications. Clin Cancer Res 13:3333–3338. doi:10.1158/1078-0432.ccr-06-3091

    Article  CAS  PubMed  Google Scholar 

  20. Wang L, Amoozgar Z, Huang J, Saleh M, Xing D, Orsulic S, Goldberg M (2015) Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol Res 3:1030–1041. doi:10.1158/2326-6066.cir-15-0073

    Article  CAS  PubMed  Google Scholar 

  21. Adair S, Hogan K (2008) 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 Immun 58:589–601. doi:10.1007/s00262-008-0582-6

    Article  Google Scholar 

  22. Coral S, Sigalotti L, Colizzi F, Spessotto A, Nardi G, Cortini E et al (2006) Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: immunotherapeutic implications. J Cell Physiol 207:58–66. doi:10.1002/jcp.20540

    Article  CAS  PubMed  Google Scholar 

  23. Sigalotti L, Fratta E, Coral S, Tanzarella S, Danielli R, Colizzi F et al (2004) Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-Aza-2′-deoxycytidine. Cancer Res 64:9167–9171. doi:10.1158/0008-5472.can-04-1442

    Article  CAS  PubMed  Google Scholar 

  24. Odunsi K, Matsuzaki J, James S, Mhawech-Fauceglia P, Tsuji T, Miller A et al (2014) Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res 2:37–49. doi:10.1158/2326-6066.cir-13-0126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gunda V, Frederick D, Bernasconi M, Wargo J, Parangi S (2014) A potential role for immunotherapy in thyroid cancer by enhancing NY-ESO-1 cancer antigen expression. Thyroid 24:1241–1250. doi:10.1089/thy.2013.0680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wachowska M, Gabrysiak M, Muchowicz A, Bednarek W, Barankiewicz J, Rygiel T et al (2014) 5-Aza-2′-deoxycytidine potentiates antitumour immune response induced by photodynamic therapy. Eur J Cancer 50:1370–1381. doi:10.1016/j.ejca.2014.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Šímová J, Polláková V, Indrová M, Mikyšková R, Bieblová J, Štěpánek I et al (2011) Immunotherapy augments the effect of 5-azacytidine on HPV16-associated tumours with different MHC class I-expression status. Br J Cancer 105:1533–1541. doi:10.1038/bjc.2011.428

    Article  PubMed  PubMed Central  Google Scholar 

  28. Krishnadas D, Bao L, Bai F, Chencheri S, Lucas K (2014) Decitabine facilitates immune recognition of sarcoma cells by upregulating CT antigens, MHC molecules, and ICAM-1. Tumor Biol 35:5753–5762. doi:10.1007/s13277-014-1764-9

    Article  CAS  Google Scholar 

  29. Natsume A, Wakabayashi T, Tsujimura K, Shimato S, Ito M, Kuzushima K et al (2008) The DNA demethylating agent 5-aza-2′-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma. Int J Cancer 122:2542–2553. doi:10.1002/ijc.23407

    Article  CAS  PubMed  Google Scholar 

  30. Coral S, Sigalotti L, Altomonte M, Engelsberg A, Cattarossi I, Maraskovsky E et al (2002) 5-aza-2′-Deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma immunotherapeutic implications. Clin Cancer Res 8:2690

    CAS  PubMed  Google Scholar 

  31. Guo Z (2006) De novo induction of a cancer/testis antigen by 5-aza-2′-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res 66:1105–1113. doi:10.1158/0008-5472.can-05-3020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gunda V, Cogdill A, Bernasconi M, Wargo J, Parangi S (2013) Potential role of 5-Aza-2′-deoxycytidine induced MAGE-A4 expression in immunotherapy for anaplastic thyroid cancer. Surgery 154:1456–1462. doi:10.1016/j.surg.2013.07.009

    Article  PubMed  Google Scholar 

  33. Ayyoub M, Taub R, Keohan M, Hesdorffer M, Metthez G, Memeo L et al (2004) The frequent expression of cancer/testis antigens provides opportunities for immunotherapeutic targeting of sarcoma. Cancer Immun 4:7

    PubMed  Google Scholar 

  34. Bao L, Dunham K, Lucas K (2011) MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells to facilitate cytotoxic T lymphocyte-mediated tumor cell killing. Cancer Immunol Immun 60:1299–1307. doi:10.1007/s00262-011-1037-z

    Article  CAS  Google Scholar 

  35. Sigalotti L, Coral S, Altomonte M, Natali L, Gaudino G, Cacciotti P et al (2002) Cancer testis antigens expression in mesothelioma: role of DNA methylation and bioimmunotherapeutic implications. Br J Cancer 86:979–982. doi:10.1038/sj.bjc.6600174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schrump D, Fischette M, Nguyen D, Zhao M, Li X, Kunst T et al (2006) Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. Clin Cancer Res 12:5777–5785. doi:10.1158/1078-0432.ccr-06-0669

    Article  CAS  PubMed  Google Scholar 

  37. Wu X, Tao Y, Hou J, Meng X, Shi J (2012) Valproic acid upregulates NKG2D ligand expression through an ERK-dependent mechanism and potentially enhances NK cell-mediated lysis of myeloma. Neoplasia 14:1178–1189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Marbach D, Costello J, Küffner R, Vega N, Prill R, Camacho D et al (2012) Wisdom of crowds for robust gene network inference. Nat Methods 9:796–804. doi:10.1038/nmeth.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tang K, He C, Zeng G, Wu J, Song G, Shi Y et al (2008) Induction of MHC class I-related chain B (MICB) by 5-aza-2′-deoxycytidine. Biochem Biophys Res Commun 370:578–583. doi:10.1016/j.bbrc.2008.03.131

    Article  CAS  PubMed  Google Scholar 

  40. Chan H, Kurago Z, Stewart C, Wilson M, Martin M, Mace B et al (2003) DNA methylation maintains allele-specific KIR gene expression in human natural killer cells. J Exp Med 197:245–255. doi:10.1084/jem.20021127

    Article  PubMed  PubMed Central  Google Scholar 

  41. Schmiedel B, Arélin V, Gruenebach F, Krusch M, Schmidt S, Salih H (2010) Azacytidine impairs NK cell reactivity while decitabine augments NK cell responsiveness toward stimulation. Int J Cancer 128:2911–2922. doi:10.1002/ijc.25635

    Article  PubMed  Google Scholar 

  42. Bruniquel D, Schwartz R (2003) Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 4:235–240. doi:10.1038/ni887

    Article  CAS  PubMed  Google Scholar 

  43. Northrop J, Thomas R, Wells A, Shen H (2006) Epigenetic remodeling of the IL-2 and IFN-loci in memory CD8 T cells is influenced by CD4 T cells. J Immunol 177:1062–1069. doi:10.4049/jimmunol.177.2.1062

    Article  CAS  PubMed  Google Scholar 

  44. Berkley A, Hendricks D, Simmons K, Fink P (2013) Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci. J Immunol 190:6180–6186. doi:10.4049/jimmunol.1300181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fitzpatrick D, Shirley K, McDonald L, Bielefeldt-Ohmann H, Kay G, Kelso A (1998) Distinct methylation of the interferon (IFN-) and interleukin 3 (IL-3) genes in newly activated primary CD8+ T lymphocytes: regional IFN- promoter demethylation and mRNA expression are heritable in CD44highCD8+ T cells. J Exp Med 188:103–117. doi:10.1084/jem.188.1.103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kersh E, Fitzpatrick D, Murali-Krishna K, Shires J, Speck S, Boss J, Ahmed R (2006) Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells. J Immunol 176:4083–4093. doi:10.4049/jimmunol.176.7.4083

    Article  CAS  PubMed  Google Scholar 

  47. Janson P, Linton L, Ahlen Bergman E, Marits P, Eberhardson M, Piehl F et al (2010) Profiling of CD4+ T cells with epigenetic immune lineage analysis. J Immunol 186:92–102. doi:10.4049/jimmunol.1000960

    Article  PubMed  Google Scholar 

  48. Costantini B, Kordasti S, Kulasekararaj A, Jiang J, Seidl T, Abellan P et al (2012) The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome. Haematologica 98:1196–1205. doi:10.3324/haematol.2012.074823

    Article  PubMed  Google Scholar 

  49. Frikeche J, Clavert A, Delaunay J, Brissot E, Grégoire M, Gaugler B, Mohty M (2011) Impact of the hypomethylating agent 5-azacytidine on dendritic cells function. Exp Hematol 39:1056–1063. doi:10.1016/j.exphem.2011.08.004

    Article  CAS  PubMed  Google Scholar 

  50. Dubovsky J, Powers J, Gao Y, Mariusso L, Sotomayor E, Pinilla-Ibarz J (2011) Epigenetic repolarization of T lymphocytes from chronic lymphocytic leukemia patients using 5-aza-2′-deoxycytidine. Leukemia Res 35:1193–1199. doi:10.1016/j.leukres.2011.02.007

    Article  CAS  Google Scholar 

  51. Sinha P, Clements V, Bunt S, Albelda S, Ostrand-Rosenberg S (2007) Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a Type 2 response. J Immunol 179:977–983. doi:10.4049/jimmunol.179.2.977

    Article  CAS  PubMed  Google Scholar 

  52. Guislain A, Gadiot J, Kaiser A, Jordanova E, Broeks A, Sanders J et al (2015) Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol Immun 64:1241–1250. doi:10.1007/s00262-015-1735-z

    Article  CAS  Google Scholar 

  53. Kim K, Skora A, Li Z, Liu Q, Tam A, Blosser R et al (2014) Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 111:11774–11779. doi:10.1073/pnas.1410626111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Triozzi P, Aldrich W, Achberger S, Ponnazhagan S, Alcazar O, Saunthararajah Y (2012) Differential effects of low-dose decitabine on immune effector and suppressor responses in melanoma-bearing mice. Cancer Immunol Immun 61:1441–1450. doi:10.1007/s00262-012-1204-x

    Article  CAS  Google Scholar 

  55. Mikysková R, Indrova M, Vlkova V, Bieblova J, Šimova J, Paračková Z et al (2014) DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment. J Leukoc Biol 95:743–753. doi:10.1189/jlb.0813435

    Article  Google Scholar 

  56. Daurkin I, Eruslanov E, Vieweg J, Kusmartsev S (2009) Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2′-deoxycytidine. Cancer Immunol Immun 59:697–706. doi:10.1007/s00262-009-0786-4

    Article  Google Scholar 

  57. Tsai H, Li H, Van Neste L, Cai Y, Robert C, Rassool F et al (2012) Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21:430–446. doi:10.1016/j.ccr.2011.12.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wrangle J, Wang W, Koch A, Easwaran H, Mohammad H, Vendetti F et al (2013) Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 4:2067–2079

    Article  PubMed  PubMed Central  Google Scholar 

  59. Li H, Chiappinelli K, Guzzetta A, Easwaran H, Yen R, Vatapalli R et al (2014) Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5:587–598

    Article  PubMed  PubMed Central  Google Scholar 

  60. Yang H, Bueso-Ramos C, DiNardo C, Estecio M, Davanlou M, Geng Q et al (2013) Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28:1280–1288. doi:10.1038/leu.2013.355

    Article  PubMed  PubMed Central  Google Scholar 

  61. Pico de Coaña Y, Choudhury A, Kiessling R (2015) Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med 21:482–491. doi:10.1016/j.molmed.2015.05.005

    Article  PubMed  Google Scholar 

  62. Paradis T, Floyd E, Burkwit J, Cole S, Brunson B, Elliott E, Gilman S, Gladue R (2001) The anti-tumor activity of anti-CTLA-4 is mediated through its induction of IFN gamma. Cancer Immunol Immunother 50:125–133

    Article  CAS  PubMed  Google Scholar 

  63. Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y et al (2012) PD-1 blockade enhances T-cell migration to tumors by elevating IFN- inducible chemokines. Cancer Res 72:5209–5218. doi:10.1158/0008-5472.can-12-1187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fan H, Lu X, Wang X, Liu Y, Guo B, Zhang Y et al (2014) Low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors: a phase I/II report. J Immunol Res 2014:371087. doi:10.1155/2014/371087

    PubMed  PubMed Central  Google Scholar 

  65. Krishnadas D, Shusterman S, Bai F, Diller L, Sullivan J, Cheerva A et al (2015) A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. Cancer Immunol Immun 64:1251–1260. doi:10.1007/s00262-015-1731-3

    Article  CAS  Google Scholar 

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Acknowledgments

We thank the Ovarian Cancer Research Fund (Liz Tilberis Scholar award) and the Susan F. Smith Center for Women’s Cancer for supporting this work.

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Authors and Affiliations

  1. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA

    Mohammad H. Saleh, Lei Wang & Michael S. Goldberg

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  1. Mohammad H. Saleh
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  2. Lei Wang
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Correspondence to Michael S. Goldberg.

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This paper is a Focussed Research Review based on a presentation given at the Fourth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2015), held in Ljubljana, Slovenia, 27th–30th April 2015. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Saleh, M.H., Wang, L. & Goldberg, M.S. Improving cancer immunotherapy with DNA methyltransferase inhibitors. Cancer Immunol Immunother 65, 787–796 (2016). https://doi.org/10.1007/s00262-015-1776-3

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