Cancer Epigenomics on Precision Medicine and Immunotherapy

  • Javier I. J. OrozcoEmail author
  • Diego M. Marzese
  • Dave S. B. Hoon
Reference work entry


Immunotherapy has rapidly become one of the most promising therapeutic approaches for cancer patients. While significantly improving patients’ survival, immunotherapy presents a unique toxicity profile. However, a large proportion of patients do not achieve optimal and durable responses, due in part to the lack of specific molecular markers that can comprehensively guide patient and therapeutic selection. Precision medicine, involving therapeutic decisions fine-tuned to the genetic makeup of an individual’s tumor, has the potential to profoundly improve the outcomes of patients treated with immunotherapy. Yet, understanding the influence of genetic variations on immunotherapy is just one aspect of developing precision medicine strategies. Epigenomics, and the advent of optimized epigenetic drugs, is emerging as a powerful tool to expand the potential of precision medicine in cancer immunotherapy. The human epigenome represents an exceptional roadmap providing a wealth of information about specific interactions between an individual’s genetic variations and environmental influences. This chapter is focused on the utility in precision medicine of epigenetic variations in the immune-response and immune-escape, and on potential applications for epigenetic therapies.


Neoplasms Epigenomics Immunotherapy Precision Medicine Biomarkers Immunomodulation Histone Deacetylase Inhibitors DNA Methyltransferase Inhibitors 

List of Abbreviations










Antigen-presenting cell




Chromatin accessibility quantitative traits loci


CpG island


Classical Hodgkin lymphoma


CGI methylator phenotype


Cancer testis antigen


Cell-free circulating tumor DNA


Cytotoxic T cells


Cytotoxic T lymphocyte-associated protein 4


Damage-associated molecular pattern


Dendritic cell


DNA methyltransferase


DNMT inhibitor


Encyclopedia of DNA Elements


Expression Quantitative Traits Loci


Enhancer of Zeste Homolog 2


Genome-wide association studies


Histone acetyltransferase


Histone deacetylases


HDAC inhibitor


Histone modification quantitative traits loci


Head and neck squamous cell carcinoma


Immunogenic cell death




Methyl-CpG-binding domain


Myeloid-derived suppressor cells


Methylation quantitative traits loci


Major histocompatibility complex


Microsatellite instability


Natural killer


Non-small-cell lung cancer


Programmed cell death-1


Programmed cell Death-Ligand 1


Posttranslational modification


Quantitative traits loci


Single-nucleotide polymorphism


Tumor-associated antigens


T cell receptor


Thymine-DNA glycosylase


Ten-eleven translocation methylcytosine dioxygenases


Transcription factor


Transcription factor quantitative traits loci


Tumor microenvironment


T regulatory cell


Tumor suppressor genes


Transcription start site



We are grateful to Dr. Ian Hutchinson for his critical revision of the manuscript and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation for their financial support.


  1. Alvarez-Errico D, Vento-Tormo R, Sieweke M et al (2015) Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol 15:7–17CrossRefGoogle Scholar
  2. Araki Y, Fann M, Wersto R et al (2008) Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B). J Immunol 180:8102–8108CrossRefGoogle Scholar
  3. Audia JE, Campbell RM (2016) Histone modifications and cancer. Cold Spring Harb Perspect Biol 8:a019521CrossRefGoogle Scholar
  4. Banovich NE, Lan X, McVicker G et al (2014) Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels. PLoS Genet 10:e1004663CrossRefGoogle Scholar
  5. Boussiotis VA (2016) Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med 375:1767–1778CrossRefGoogle Scholar
  6. Cairns P (2007) Gene methylation and early detection of genitourinary cancer: the road ahead. Nat Rev Cancer 7:531–543CrossRefGoogle Scholar
  7. Campoli M, Ferrone S (2008) HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene 27:5869–5885CrossRefGoogle Scholar
  8. Chapelle A, Hampel H (2010) Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol 28:3380–3387CrossRefGoogle Scholar
  9. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10CrossRefGoogle Scholar
  10. Chiappinelli KB, Strissel PL, Desrichard A et al (2015) Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162:974–986CrossRefGoogle Scholar
  11. Chiappinelli KB, Zahnow CA, Ahuja N et al (2016) Combining epigenetic and immunotherapy to combat cancer. Cancer Res 76:1683–1689CrossRefGoogle Scholar
  12. Clozel T, Yang S, Elstrom RL et al (2013) Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov 3:1002–1019CrossRefGoogle Scholar
  13. Collins FS, Varmus H (2015) A new initiative on precision medicine. N Engl J Med 372:793–795CrossRefGoogle Scholar
  14. de Maat MF, van de Velde CJ, van der Werff MP et al (2008) Quantitative analysis of methylation of genomic loci in early-stage rectal cancer predicts distant recurrence. J Clin Oncol 26(14):2327–35CrossRefGoogle Scholar
  15. de Gramont A, Watson S, Ellis LM et al (2015) Pragmatic issues in biomarker evaluation for targeted therapies in cancer. Nat Rev Clin Oncol 12:197–212CrossRefGoogle Scholar
  16. Doi A, Park IH, Wen B et al (2009) Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41:1350–1353CrossRefGoogle Scholar
  17. ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74CrossRefGoogle Scholar
  18. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159CrossRefGoogle Scholar
  19. Esteller M, Garcia-Foncillas J, Andion E et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354CrossRefGoogle Scholar
  20. Flavahan WA, Drier Y, Liau BB et al (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529:110–114CrossRefGoogle Scholar
  21. Garraway LA, Lander ES (2013) Lessons from the cancer genome. Cell 153:17–37CrossRefGoogle Scholar
  22. Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefGoogle Scholar
  23. van Hoesel AQ, Sato Y, Elashoff DA et al (2013) Assessment of DNA methylation status in early stages of breast cancer development. Br J Cancer 108:2033–2038CrossRefGoogle Scholar
  24. Hoshimoto S, Takeuchi H, Ono S et al (2015) Genome-wide hypomethylation and specific tumor-related gene hypermethylation are associated with esophageal squamous cell carcinoma outcome. J Thorac Oncol 10:509–517CrossRefGoogle Scholar
  25. Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41:178–186CrossRefGoogle Scholar
  26. Jones PA, Issa JP, Baylin S (2016) Targeting the cancer epigenome for therapy. Nat Rev Genet 17:630–641CrossRefGoogle Scholar
  27. Kim JM, Chen DS (2016) Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol 27:1492–1504CrossRefGoogle Scholar
  28. Kim K, Skora AD, Li Z et al (2014) Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 111:11774–11779CrossRefGoogle Scholar
  29. Kopp LM, Ray A, Denman CJ et al (2013) Decitabine has a biphasic effect on natural killer cell viability, phenotype, and function under proliferative conditions. Mol Immunol 54:296–301CrossRefGoogle Scholar
  30. Krysko DV, Garg AD, Kaczmarek A et al (2012) Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 12:860–875CrossRefGoogle Scholar
  31. Lian CG, Xu Y, Ceol C et al (2012) Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150:1135–1146CrossRefGoogle Scholar
  32. Lopez-Soto A, Folgueras AR, Seto E et al (2009) HDAC3 represses the expression of NKG2D ligands ULBPs in epithelial tumour cells: potential implications for the immunosurveillance of cancer. Oncogene 28:2370–2382CrossRefGoogle Scholar
  33. Maecker HL, Yun Z, Maecker HT et al (2002) Epigenetic changes in tumor Fas levels determine immune escape and response to therapy. Cancer Cell 2:139–148CrossRefGoogle Scholar
  34. Maio M, Covre A, Fratta E et al (2015) Molecular pathways: at the crossroads of cancer epigenetics and immunotherapy. Clin Cancer Res 21:4040–4047CrossRefGoogle Scholar
  35. Marzese DM, Hirose H, Hoon DS (2013) Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients. Expert Rev Mol Diagn 13:827–844CrossRefGoogle Scholar
  36. Marzese DM, Scolyer RA, Huynh JL et al (2014) Epigenome-wide DNA methylation landscape of melanoma progression to brain metastasis reveals aberrations on homeobox D cluster associated with prognosis. Hum Mol Genet 23:226–238CrossRefGoogle Scholar
  37. Moran S, Martinez-Cardus A, Sayols S et al (2016) Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 17:1386–1395CrossRefGoogle Scholar
  38. Mori T, O’Day SJ, Umetani N et al (2005) Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy. J Clin Oncol 23:9351–9358CrossRefGoogle Scholar
  39. Noushmehr H, Weisenberger DJ, Diefes K et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522CrossRefGoogle Scholar
  40. Odunsi K, Matsuzaki J, James SR et al (2014) Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res 2:37–49CrossRefGoogle Scholar
  41. Ogino S, Kawasaki T, Kirkner GJ et al (2007) Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagn 9:305–314CrossRefGoogle Scholar
  42. Ogino S, Galon J, Fuchs CS et al (2011) Cancer immunology-analysis of host and tumor factors for personalized medicine. Nat Rev Clin Oncol 8:711–719CrossRefGoogle Scholar
  43. Palucka AK, Coussens LM (2016) The basis of oncoimmunology. Cell 164:1233–1247CrossRefGoogle Scholar
  44. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264CrossRefGoogle Scholar
  45. Peng D, Kryczek I, Nagarsheth N et al (2015) Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527:249–253CrossRefGoogle Scholar
  46. Qiu J, Peng B, Tang Y et al (2017) CpG methylation signature predicts recurrence in early-stage hepatocellular carcinoma: results from a multicenter study. J Clin Oncol 35:734–742CrossRefGoogle Scholar
  47. Rodriguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17:330–339CrossRefGoogle Scholar
  48. Roulois D, Loo Yau H, Singhania R et al (2015) DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162:961–973CrossRefGoogle Scholar
  49. Schadendorf D, Hodi FS, Robert C et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of Ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33:1889–1894CrossRefGoogle Scholar
  50. Scharer CD, Barwick BG, Youngblood BA et al (2013) Global DNA methylation remodeling accompanies CD8 T cell effector function. J Immunol 191:3419–3429CrossRefGoogle Scholar
  51. Schmidl C, Klug M, Boeld TJ et al (2009) Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 19:1165–1174CrossRefGoogle Scholar
  52. Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161:205–214CrossRefGoogle Scholar
  53. Shen J, Wang S, Zhang YJ et al (2013) Exploring genome-wide DNA methylation profiles altered in hepatocellular carcinoma using Infinium HumanMethylation 450 BeadChips. Epigenetics 8:34–43CrossRefGoogle Scholar
  54. Sigalotti L, Fratta E, Coral S et al (2014) Epigenetic drugs as immunomodulators for combination therapies in solid tumors. Pharmacol Ther 142:339–350CrossRefGoogle Scholar
  55. Simpson AJ, Caballero OL, Jungbluth A et al (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5:615–625CrossRefGoogle Scholar
  56. Stunnenberg HG, International Human Epigenome C, Hirst M (2016) The international human epigenome consortium: a blueprint for scientific collaboration and discovery. Cell 167:1145–1149CrossRefGoogle Scholar
  57. Tahiliani M, Koh KP, Shen Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935CrossRefGoogle Scholar
  58. Talbert PB, Henikoff S (2010) Histone variants–ancient wrap artists of the epigenome. Nat Rev Mol Cell Biol 11:264–275CrossRefGoogle Scholar
  59. Tanemura A, Terando AM, Sim MS et al (2009) CpG island methylator phenotype predicts progression of malignant melanoma. Clin Cancer Res 15:1801–1807CrossRefGoogle Scholar
  60. Tough DF, Tak PP, Tarakhovsky A et al (2016) Epigenetic drug discovery: breaking through the immune barrier. Nat Rev Drug Discov 15:835–853CrossRefGoogle Scholar
  61. Trynka G, Sandor C, Han B et al (2013) Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet 45:124–130CrossRefGoogle Scholar
  62. Vivier E, Raulet DH, Moretta A et al (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49CrossRefGoogle Scholar
  63. Wang L, Amoozgar Z, Huang J et al (2015) Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol Res 3:1030–1041CrossRefGoogle Scholar
  64. Wang C, Gu Y, Zhang K et al (2016a) Systematic identification of genes with a cancer-testis expression pattern in 19 cancer types. Nat Commun 7:10499CrossRefGoogle Scholar
  65. Wang J, Wang H, Wang LY et al (2016b) Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. Cell Death Differ 23:1886–1896CrossRefGoogle Scholar
  66. Warton K, Mahon KL, Samimi G (2016) Methylated circulating tumor DNA in blood: power in cancer prognosis and response. Endocr Relat Cancer 23:R157–R171CrossRefGoogle Scholar
  67. Welter D, MacArthur J, Morales J et al (2014) The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42:D1001–D1006CrossRefGoogle Scholar
  68. West AC, Mattarollo SR, Shortt J et al (2013) An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Res 73:7265–7276CrossRefGoogle Scholar
  69. Woods DM, Sodre AL, Villagra A et al (2015) HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 3:1375–1385CrossRefGoogle Scholar
  70. Zhang Y, Kinkel S, Maksimovic J et al (2014) The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood 124:737–749CrossRefGoogle Scholar
  71. Zheng H, Zhao W, Yan C et al (2016) HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin Cancer Res 22:4119–4132CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Javier I. J. Orozco
    • 1
    Email author
  • Diego M. Marzese
    • 1
  • Dave S. B. Hoon
    • 1
  1. 1.Department of Translational Molecular MedicineJohn Wayne Cancer Institute at Providence Saint John’s Health CenterSanta MonicaUSA

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