Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy

Journal of Pathology

Volumn 241, Issue 1, 2017, Pages 10-24

  Liu, Man ^a   Zhou, Jingying ^a   Chen, Zhiwei ^b   Cheng, Alfred Sze Lok ^a  

^a CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

^b UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

cancer associated fibroblast; cytotoxic T lymphocyte; dendritic cell; DNA demethylating agents; histone deacetylase inhibitors; macrophage; mesenchymal stem cell; microRNA; myeloid derived suppressor cell; natural killer cell; regulatory T cell; tumour associated antigens

Indexed keywords

DECITABINE; DNA METHYLTRANSFERASE INHIBITOR; HISTONE DEACETYLASE INHIBITOR;

CANCER CELL; CANCER IMMUNOTHERAPY; EFFECTOR CELL; EPIGENETICS; GENE SILENCING; GENE THERAPY; GENETIC REGULATION; HUMAN; IMMUNE EVASION; IMMUNOCOMPETENT CELL; IMMUNOGENICITY; IMMUNOSUPPRESSIVE TREATMENT; MYELOID DERIVED SUPPRESSOR CELL; MYELOID PROGENITOR CELL; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; STROMA CELL; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; CYTOTOXIC T LYMPHOCYTE; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETICS; IMMUNOLOGY; IMMUNOTHERAPY; NEOPLASMS; PROCEDURES; TUMOR ESCAPE;

EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; IMMUNOTHERAPY; NEOPLASMS; T-LYMPHOCYTES, CYTOTOXIC; TUMOR ESCAPE; TUMOR MICROENVIRONMENT;

EID: 85006141145     PISSN: 00223417     EISSN: 10969896     Source Type: Journal    
DOI: 10.1002/path.4832     Document Type: Review

References (204)

1. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013; 14: 1014–1022.
2. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004; 21: 137–148.
3. Becker JC, Andersen MH, Schrama D, et al. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol Immunother 2013; 62: 1137–1148.
4. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl) 2013; 91: 431–437.
5. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015; 33: 1974–1982.
6. Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 2013; 501: 346–354.
7. Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science 2015; 348: 74–80.
8. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell 2012; 150: 12–27.
9. Hellebrekers DM, Castermans K, Vire E, et al. Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications. Cancer Res 2006; 66: 10770–10777.
10. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.
11. 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.
12. Sigalotti L, Fratta E, Coral S, et al. Epigenetic drugs as immunomodulators for combination therapies in solid tumors. Pharmacol Ther 2014; 142: 339–350.
13. Schubeler D. Function and information content of DNA methylation. Nature 2015; 517: 321–326.
14. Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer 2013; 13: 497–510.
15. Christman JK. 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 2002; 21: 5483–5495.
16. Weishaupt H, Sigvardsson M, Attema JL. Epigenetic chromatin states uniquely define the developmental plasticity of murine hematopoietic stem cells. Blood 2010; 115: 247–256.
17. Eberharter A, Becker PB. Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep 2002; 3: 224–229.
18. Chang S, Aune TM. Dynamic changes in histone-methylation ‘marks’ across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. Nat Immunol 2007; 8: 723–731.
19. Nencioni A, Beck J, Werth D, et al. Histone deacetylase inhibitors affect dendritic cell differentiation and immunogenicity. Clin Cancer Res 2007; 13: 3933–3941.
20. Kouzarides T. Histone methylation in transcriptional control. Curr Opin Genet Dev 2002; 12: 198–209.
21. McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492: 108–112.
22. Ambros V. The functions of animal microRNAs. Nature 2004; 431: 350–355.
23. Simpson LJ, Ansel KM. MicroRNA regulation of lymphocyte tolerance and autoimmunity. J Clin Invest 2015; 125: 2242–2249.
24. Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 2012; 4: 143–159.
25. Zampetaki A, Mayr M. MicroRNAs in vascular and metabolic disease. Circ Res 2012; 110: 508–522.
26. O'Connell RM, Rao DS, Chaudhuri AA, et al. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 2010; 10: 111–122.
27. Rusek AM, Abba M, Eljaszewicz A, et al. MicroRNA modulators of epigenetic regulation, the tumor microenvironment and the immune system in lung cancer. Mol Cancer 2015; 14: 34.
28. Schickel R, Boyerinas B, Park SM, et al. MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 2008; 27: 5959–5974.
29. Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991–998.
30. Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2015; 21: 687–692.
31. El Hage F, Durgeau A, Mami-Chouaib F. TAP expression level in tumor cells defines the nature and processing of MHC class I peptides for recognition by tumor-specific cytotoxic T lymphocytes. Ann N Y Acad Sci 2013; 1283: 75–80.
32. Kusmartsev S, Gabrilovich DI. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metast Rev 2006; 25: 323–331.
33. Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer 2013; 13: 739–752.
34. Ostrand-Rosenberg S, Sinha P, Beury DW, et al. Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol 2012; 22: 275–281.
35. Pan PY, Ma G, Weber KJ, et al. Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 2010; 70: 99–108.
36. Franklin RA, Liao W, Sarkar A, et al. The cellular and molecular origin of tumor-associated macrophages. Science 2014; 344: 921–925.
37. Ugel S, De Sanctis F, Mandruzzato S, et al. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest 2015; 125: 3365–3376.
38. Geissmann F, Manz MG, Jung S, et al. Development of monocytes, macrophages, and dendritic cells. Science 2010; 327: 656–661.
39. Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016; 7: 12150.
40. Rigamonti N, Capuano G, Ricupito A, et al. Modulators of arginine metabolism do not impact on peripheral T-cell tolerance and disease progression in a model of spontaneous prostate cancer. Clin Cancer Res 2011; 17: 1012–1023.
41. Haverkamp JM, Smith AM, Weinlich R, et al. Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways. Immunity 2014; 41: 947–959.
42. Strauss L, Sangaletti S, Consonni FM, et al. RORC1 regulates tumor-promoting ‘emergency’ granulo-monocytopoiesis. Cancer Cell 2015; 28: 253–269.
43. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8: 523–532.
44. Tan W, Zhang W, Strasner A, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling. Nature 2011; 470: 548–553.
45. Chen WJ, Ho CC, Chang YL, et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat Commun 2014; 5: 3472.
46. Mace TA, Ameen Z, Collins A, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 2013; 73: 3007–3018.
47. Comito G, Giannoni E, Segura CP, et al. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene 2014; 33: 2423–2431.
48. Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010; 330: 827–830.
49. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557–563.
50. Bergfeld SA, DeClerck YA. Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Cancer Metast Rev 2010; 29: 249–261.
51. Lee HJ, Ko JH, Jeong HJ, et al. Mesenchymal stem/stromal cells protect against autoimmunity via CCL2-dependent recruitment of myeloid-derived suppressor cells. J Immunol 2015; 194: 3634–3645.
52. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer 2012; 12: 265–277.
53. Ma Y, Shurin GV, Gutkin DW, et al. Tumor associated regulatory dendritic cells. Semin Cancer Biol 2012; 22: 298–306.
54. Schietinger A, Philip M, Krisnawan VE, et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 2016; 45: 389–401.
55. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27: 450–461.
56. Topalian SL, Wolchok JD, Chan TA, et al. Immunotherapy: the path to win the war on cancer? Cell 2015; 161: 185–186.
57. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002; 99: 12293–12297.
58. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–264.
59. Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol 2016; 17: 1025–1036.
60. Takeuchi H, Maehara Y, Tokunaga E, et al. Prognostic significance of natural killer cell activity in patients with gastric carcinoma: a multivariate analysis. Am J Gastroenterol 2001; 96: 574–578.
61. Sznurkowski JJ, Zawrocki A, Biernat W. Subtypes of cytotoxic lymphocytes and natural killer cells infiltrating cancer nests correlate with prognosis in patients with vulvar squamous cell carcinoma. Cancer Immunol Immunother 2014; 63: 297–303.
62. Pasero C, Gravis G, Guerin M, et al. Inherent and tumor-driven immune tolerance in the prostate microenvironment impairs natural killer cell antitumor activity. Cancer Res 2016; 76: 2153–2165.
63. Li H, Han Y, Guo Q, et al. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 2009; 182: 240–249.
64. Liu C, Yu S, Kappes J, et al. Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood 2007; 109: 4336–4342.
65. Hasmim M, Messai Y, Ziani L, et al. Critical role of tumor microenvironment in shaping NK cell functions: implication of hypoxic stress. Front Immunol 2015; 6: 482.
66. Wachowska M, Gabrysiak M, Golab J. Epigenetic remodeling combined with photodynamic therapy elicits anticancer immune responses. Oncoimmunology 2014; 3: e28837.
67. Setiadi AF, David MD, Seipp RP, et al. Epigenetic control of the immune escape mechanisms in malignant carcinomas. Mol Cell Biol 2007; 27: 7886–7894.
68. Wrangle J, Wang W, Koch A, et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 2013; 4: 2067–2079.
69. Doorduijn EM, Sluijter M, Querido BJ, et al. TAP-independent self-peptides enhance T cell recognition of immune-escaped tumors. J Clin Invest 2016; 126: 784–794.
70. Watson NF, Ramage JM, Madjd Z, et al. Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int J Cancer 2006; 118: 6–10.
71. Seliger B, Stoehr R, Handke D, et al. Association of HLA class I antigen abnormalities with disease progression and early recurrence in prostate cancer. Cancer Immunol Immunother 2010; 59: 529–540.
72. Skov S, Pedersen MT, Andresen L, et al. Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B. Cancer Res 2005; 65: 11136–11145.
73. Simova J, Pollakova V, Indrova M, et al. Immunotherapy augments the effect of 5-azacytidine on HPV16-associated tumours with different MHC class I-expression status. Br J Cancer 2011; 105: 1533–1541.
74. Vlkova V, Stepanek I, Hruskova V, et al. Epigenetic regulations in the IFNgamma signalling pathway: IFNgamma-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes. Oncotarget 2014; 5: 6923–6935.
75. Walkley CR, Shea JM, Sims NA, et al. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 2007; 129: 1081–1095.
76. Youn JI, Kumar V, Collazo M, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 2013; 14: 211–220.
77. Sahakian E, Powers JJ, Chen J, et al. Histone deacetylase 11: a novel epigenetic regulator of myeloid derived suppressor cell expansion and function. Mol Immunol 2015; 63: 579–585.
78. Villagra A, Cheng F, Wang HW, et al. The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol 2009; 10: 92–100.
79. Beury DW, Parker KH, Nyandjo M, et al. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J Leukoc Biol 2014; 96: 1109–1118.
80. Rosborough BR, Castellaneta A, Natarajan S, et al. Histone deacetylase inhibition facilitates GM-CSF-mediated expansion of myeloid-derived suppressor cells in vitro and in vivo. J Leukoc Biol 2012; 91: 701–709.
81. Sido JM, Yang X, Nagarkatti PS, et al. Delta9-Tetrahydrocannabinol-mediated epigenetic modifications elicit myeloid-derived suppressor cell activation via STAT3/S100A8. J Leukoc Biol 2015; 97: 677–688.
82. Zhang M, Liu Q, Mi S, et al. Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. J Immunol 2011; 186: 4716–4724.
83. Liu Y, Lai L, Chen Q, et al. MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. J Immunol 2012; 188: 5500–5510.
84. Tian J, Rui K, Tang X, et al. MicroRNA-9 regulates the differentiation and function of myeloid-derived suppressor cells via targeting Runx1. J Immunol 2015; 195: 1301–1311.
85. Li L, Zhang J, Diao W, et al. MicroRNA-155 and MicroRNA-21 promote the expansion of functional myeloid-derived suppressor cells. J Immunol 2014; 192: 1034–1043.
86. Noman MZ, Janji B, Hu S, et al. Tumor-promoting effects of myeloid-derived suppressor cells are potentiated by hypoxia-induced expression of miR-210. Cancer Res 2015; 75: 3771–3787.
87. Liu Q, Zhang M, Jiang X, et al. miR-223 suppresses differentiation of tumor-induced CD11b(+) Gr1(+) myeloid-derived suppressor cells from bone marrow cells. Int J Cancer 2011; 129: 2662–2673.
88. Hegde VL, Tomar S, Jackson A, et al. Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Delta9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein alpha by microRNA-690. J Biol Chem 2013; 288: 36810–36826.
89. McClure C, Brudecki L, Ferguson DA, et al. MicroRNA 21 (miR-21) and miR-181b couple with NFI-A to generate myeloid-derived suppressor cells and promote immunosuppression in late sepsis. Infect Immun 2014; 82: 3816–3825.
90. Ivashkiv LB. Epigenetic regulation of macrophage polarization and function. Trends Immunol 2013; 34: 216–223.
91. Ishii M, Wen H, Corsa CA, et al. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 2009; 114: 3244–3254.
92. Osawa T, Tsuchida R, Muramatsu M, et al. Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages. Cancer Res 2013; 73: 3019–3028.
93. Chang YC, Chen TC, Lee CT, et al. Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3. Blood 2008; 111: 5054–5063.
94. He M, Xu Z, Ding T, et al. MicroRNA-155 regulates inflammatory cytokine production in tumor-associated macrophages via targeting C/EBPbeta. Cell Mol Immunol 2009; 6: 343–352.
95. Xu Z, Zhao L, Zhu LY, et al. MicroRNA-17, 20a regulates the proangiogenic function of tumor-associated macrophages via targeting hypoxia-inducible factor 2alpha. PLoS One 2013; 8: e77890.
96. Squadrito ML, Pucci F, Magri L, et al. miR-511-3p modulates genetic programs of tumor-associated macrophages. Cell Rep 2012; 1: 141–154.
97. Yang J, Zhang Z, Chen C, et al. MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene. Oncogene 2014; 33: 3014–3023.
98. Waight JD, Takai S, Marelli B, et al. Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans. J Immunol 2015; 194: 878–882.
99. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity 2013; 38: 414–423.
100. Ohkura N, Hamaguchi M, Morikawa H, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 2012; 37: 785–799.
101. DuPage M, Chopra G, Quiros J, et al. The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity 2015; 42: 227–238.
102. Nagata DE, Ting HA, Cavassani KA, et al. Epigenetic control of Foxp3 by SMYD3 H3K4 histone methyltransferase controls iTreg development and regulates pathogenic T-cell responses during pulmonary viral infection. Mucosal Immunol 2015; 8: 1131–1143.
103. Yin Y, Cai X, Chen X, et al. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res 2014; 24: 1164–1180.
104. Li W, Kong LB, Li JT, et al. MiR-568 inhibits the activation and function of CD4(+) T cells and Treg cells by targeting NFAT5. Int Immunol 2014; 26: 269–281.
105. Qin A, Wen Z, Zhou Y, et al. MicroRNA-126 regulates the induction and function of CD4(+) Foxp3(+) regulatory T cells through PI3K/AKT pathway. J Cell Mol Med 2013; 17: 252–264.
106. Fiegl H, Millinger S, Goebel G, et al. Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer. Cancer Res 2006; 66: 29–33.
107. Jiang L, Gonda TA, Gamble MV, et al. Global hypomethylation of genomic DNA in cancer-associated myofibroblasts. Cancer Res 2008; 68: 9900–9908.
108. Tyan SW, Hsu CH, Peng KL, et al. Breast cancer cells induce stromal fibroblasts to secrete ADAMTS1 for cancer invasion through an epigenetic change. PLoS One 2012; 7: e35128.
109. Pazolli E, Alspach E, Milczarek A, et al. Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res 2012; 72: 2251–2261.
110. Aprelikova O, Palla J, Hibler B, et al. Silencing of miR-148a in cancer-associated fibroblasts results in WNT10B-mediated stimulation of tumor cell motility. Oncogene 2013; 32: 3246–3253.
111. Aprelikova O, Yu X, Palla J, et al. The role of miR-31 and its target gene SATB2 in cancer-associated fibroblasts. Cell Cycle 2010; 9: 4387–4398.
112. Musumeci M, Coppola V, Addario A, et al. Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer. Oncogene 2011; 30: 4231–4242.
113. Lee S, Kim HS, Roh KH, et al. DNA methyltransferase inhibition accelerates the immunomodulation and migration of human mesenchymal stem cells. Sci Rep 2015; 5: 8020.
114. Liu L, Wang Y, Fan H, et al. MicroRNA-181a regulates local immune balance by inhibiting proliferation and immunosuppressive properties of mesenchymal stem cells. Stem Cells 2012; 30: 1756–1770.
115. Rosenzweig JM, Glenn JD, Calabresi PA, et al. KLF4 modulates expression of IL-6 in dendritic cells via both promoter activation and epigenetic modification. J Biol Chem 2013; 288: 23868–23874.
116. Won H, Nandakumar V, Yates P, et al. Epigenetic control of dendritic cell development and fate determination of common myeloid progenitor by Mysm1. Blood 2014; 124: 2647–2656.
117. Zhang X, Ulm A, Somineni HK, et al. DNA methylation dynamics during ex vivo differentiation and maturation of human dendritic cells. Epigenetics Chromatin 2014; 7: 21.
118. Huang Y, Min S, Lui Y, et al. Global mapping of H3K4me3 and H3K27me3 reveals chromatin state-based regulation of human monocyte-derived dendritic cells in different environments. Genes Immun 2012; 13: 311–320.
119. Liang X, Liu Y, Mei S, et al. MicroRNA-22 impairs anti-tumor ability of dendritic cells by targeting p38. PLoS One 2015; 10: e0121510.
120. Du J, Wang J, Tan G, et al. Aberrant elevated microRNA-146a in dendritic cells (DC) induced by human pancreatic cancer cell line BxPC-3-conditioned medium inhibits DC maturation and activation. Med Oncol 2012; 29: 2814–2823.
121. Park H, Huang X, Lu C, et al. MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. J Biol Chem 2015; 290: 2831–2841.
122. Lee PP, Fitzpatrick DR, Beard C, et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 2001; 15: 763–774.
123. de Araujo-Souza PS, Hanschke SC, Viola JP. Epigenetic control of interferon-gamma expression in CD8 T cells. J Immunol Res 2015; 2015: 849573.
124. Harland KL, Day EB, Apte SH, et al. Epigenetic plasticity of Cd8a locus during CD8(+) T-cell development and effector differentiation and reprogramming. Nat Commun 2014; 5: 3547.
125. Denton AE, Russ BE, Doherty PC, et al. Differentiation-dependent functional and epigenetic landscapes for cytokine genes in virus-specific CD8+ T cells. Proc Natl Acad Sci USA 2011; 108: 15306–15311.
126. Ahn E, Youngblood B, Lee J, et al. Demethylation of the PD-1 promoter is imprinted during the effector phase of CD8 T cell exhaustion. J Virol 2016; 90: 8934–8946.
127. Wu J, Xu X, Lee EJ, et al. Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming. Oncotarget 2016; 7: 40558–40570.
128. Lin R, Chen L, Chen G, et al. Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression. J Clin Invest 2014; 124: 5352–5367.
129. Yu T, Zuo QF, Gong L, et al. MicroRNA-491 regulates the proliferation and apoptosis of CD8(+) T cells. Sci Rep 2016; 6: 30923.
130. Santourlidis S, Trompeter HI, Weinhold S, et al. Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells. J Immunol 2002; 169: 4253–4261.
131. Santourlidis S, Graffmann N, Christ J, et al. Lineage-specific transition of histone signatures in the killer cell Ig-like receptor locus from hematopoietic progenitor to NK cells. J Immunol 2008; 180: 418–425.
132. Yin J, Leavenworth JW, Li Y, et al. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci USA 2015; 112: 15988–15993.
133. Donatelli SS, Zhou JM, Gilvary DL, et al. TGF-beta-inducible microRNA-183 silences tumor-associated natural killer cells. Proc Natl Acad Sci USA 2014; 111: 4203–4208.
134. Berchem G, Noman MZ, Bosseler M, et al. Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-beta and miR23a transfer. Oncoimmunology 2016; 5: e1062968.
135. Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 2006; 5: 37–50.
136. Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol 2016; 8: a019505.
137. Heninger E, Krueger TE, Lang JM. Augmenting antitumor immune responses with epigenetic modifying agents. Front Immunol 2015; 6: 29.
138. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 2006; 108: 3271–3279.
139. Kelly WK, Richon VM, O'Connor O, et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003; 9: 3578–3588.
140. Kelly WK, O'Connor OA, Krug LM, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005; 23: 3923–3931.
141. James SR, Link PA, Karpf AR. Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b. Oncogene 2006; 25: 6975–6985.
142. Dubovsky JA, McNeel DG. Inducible expression of a prostate cancer-testis antigen, SSX-2, following treatment with a DNA methylation inhibitor. Prostate 2007; 67: 1781–1790.
143. Weber J, Salgaller M, Samid D, et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine. Cancer Res 1994; 54: 1766–1771.
144. Natsume A, Wakabayashi T, Tsujimura K, et al. The DNA demethylating agent 5-aza-2′-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma. Int J Cancer 2008; 122: 2542–2553.
145. Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, et al. The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk Res 2010; 34: 899–905.
146. Zhang QM, Shen N, Xie S, et al. MAGED4 expression in glioma and upregulation in glioma cell lines with 5-aza-2′-deoxycytidine treatment. Asian Pac J Cancer Prev 2014; 15: 3495–3501.
147. Kim KM, Song MH, Kim MJ, et al. A novel cancer/testis antigen KP-OVA-52 identified by SEREX in human ovarian cancer is regulated by DNA methylation. Int J Oncol 2012; 41: 1139–1147.
148. Filho PA, Lopez-Albaitero A, Xi L, et al. Quantitative expression and immunogenicity of MAGE-3 and −6 in upper aerodigestive tract cancer. Int J Cancer 2009; 125: 1912–1920.
149. Zhou J, Li Y, Yao Y, et al. The cancer testis antigen NXF2 is activated by the hypomethylating agent decitabine in acute leukemia cells in vitro and in vivo. Mol Med Rep 2013; 8: 1549–1555.
150. Fonsatti E, Nicolay HJ, Sigalotti L, et al. Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2′-deoxycytidine in cutaneous melanoma: immunotherapeutic implications. Clin Cancer Res 2007; 13: 3333–3338.
151. Guo ZS, Hong JA, Irvine KR, et al. De novo induction of a cancer/testis antigen by 5-aza-2′-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res 2006; 66: 1105–1113.
152. Serrano A, Tanzarella S, Lionello I, et al. Rexpression of HLA class I antigens and restoration of antigen-specific CTL response in melanoma cells following 5-aza-2′-deoxycytidine treatment. Int J Cancer 2001; 94: 243–251.
153. Wang LX, Mei ZY, Zhou JH, et al. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. PLoS One 2013; 8: e62924.
154. Serrano A, Castro-Vega I, Redondo M. Role of gene methylation in antitumor immune response: implication for tumor progression. Cancers (Basel) 2011; 3: 1672–1690.
155. Mikyskova R, Indrova M, Vlkova V, et al. DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment. J Leukoc Biol 2014; 95: 5743–5753.
156. Daurkin I, Eruslanov E, Vieweg J, et al. Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2′-deoxycytidine. Cancer Immunol Immunother 2010; 59: 697–706.
157. Frikeche J, Clavert A, Delaunay J, et al. Impact of the hypomethylating agent 5-azacytidine on dendritic cells function. Exp Hematol 2011; 39: 1056–1063.
158. Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015; 527: 249–253.
159. 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.
160. Yang H, Bueso-Ramos C, DiNardo C, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 2014; 28: 1280–1288.
161. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 2014; 124: 30–39.
162. Kroesen M, Gielen P, Brok IC, et al. HDAC inhibitors and immunotherapy; a double edged sword? Oncotarget 2014; 5: 6558–6572.
163. Magner WJ, Kazim AL, Stewart C, et al. Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J Immunol 2000; 165: 7017–7024.
164. Cycon KA, Mulvaney K, Rimsza LM, et al. Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma. Immunology 2013; 140: 259–272.
165. West AC, Christiansen AJ, Smyth MJ, et al. The combination of histone deacetylase inhibitors with immune-stimulating antibodies has potent anti-cancer effects. Oncoimmunology 2012; 1: 377–379.
166. Maeda T, Towatari M, Kosugi H, et al. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 2000; 96: 3847–3856.
167. Murakami T, Sato A, Chun NA, et al. Transcriptional modulation using HDACi depsipeptide promotes immune cell-mediated tumor destruction of murine B16 melanoma. J Invest Dermatol 2008; 128: 1506–1516.
168. Manning J, Indrova M, Lubyova B, et al. Induction of MHC class I molecule cell surface expression and epigenetic activation of antigen-processing machinery components in a murine model for human papilloma virus 16-associated tumours. Immunology 2008; 123: 218–227.
169. Setiadi AF, Omilusik K, David MD, et al. Epigenetic enhancement of antigen processing and presentation promotes immune recognition of tumors. Cancer Res 2008; 68: 9601–9607.
170. Chou SD, Khan AN, Magner WJ, et al. Histone acetylation regulates the cell type specific CIITA promoters, MHC class II expression and antigen presentation in tumor cells. Int Immunol 2005; 17: 1483–1494.
171. Woods DM, Woan K, Cheng F, et al. The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity. Melanoma Res 2013; 23: 341–348.
172. Armeanu S, Bitzer M, Lauer UM, et al. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res 2005; 65: 6321–6329.
173. Choi S, Reddy P. HDAC inhibition and graft versus host disease. Mol Med 2011; 17: 404–416.
174. Glauben R, Batra A, Fedke I, et al. Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 2006; 176: 5015–5022.
175. Lohman RJ, Iyer A, Fairlie TJ, et al. Differential anti-inflammatory activity of HDAC inhibitors in human macrophages and rat arthritis. J Pharmacol Exp Ther 2016; 356: 387–396.
176. Misaki K, Morinobu A, Saegusa J, et al. Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice. Arthritis Res Ther 2011; 13: R77.
177. Tao R, de Zoeten EF, Ozkaynak E, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 2007; 13: 1299–1307.
178. Donas C, Fritz M, Manriquez V, et al. Trichostatin A promotes the generation and suppressive functions of regulatory T cells. Clin Dev Immunol 2013; 2013: 679804.
179. Akimova T, Ge G, Golovina T, et al. Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs. Clin Immunol 2010; 136: 348–363.
180. de Zoeten EF, Wang L, Sai H, et al. Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice. Gastroenterology 2010; 138: 583–594.
181. Kalin JH, Butler KV, Akimova T, et al. Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells. J Med Chem 2012; 55: 639–651.
182. Reddy P. HDAC inhibition begets more MDSCs. J Leukoc Biol 2012; 91: 679–681.
183. Reddy P, Sun Y, Toubai T, et al. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest 2008; 118: 2562–2573.
184. Sun Y, Chin YE, Weisiger E, et al. Cutting edge: negative regulation of dendritic cells through acetylation of the nonhistone protein STAT-3. J Immunol 2009; 182: 5899–5903.
185. Rossi LE, Avila DE, Spallanzani RG, et al. Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. J Leukoc Biol 2012; 91: 321–331.
186. Bode KA, Schroder K, Hume DA, et al. Histone deacetylase inhibitors decrease Toll-like receptor-mediated activation of proinflammatory gene expression by impairing transcription factor recruitment. Immunology 2007; 122: 596–606.
187. Roger T, Lugrin J, Le Roy D, et al. Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection. Blood 2011; 117: 1205–1217.
188. Brogdon JL, Xu Y, Szabo SJ, et al. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 2007; 109: 1123–1130.
189. Mosley AJ, Meekings KN, McCarthy C, et al. Histone deacetylase inhibitors increase virus gene expression but decrease CD8+ cell antiviral function in HTLV-1 infection. Blood 2006; 108: 3801–3807.
190. Woods DM, Sodre AL, Villagra A, et al. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 2015; 3: 1375–1385.
191. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480: 480–489.
192. Greene JM, Schneble EJ, Jackson DO, et al. A phase I/IIa clinical trial in stage IV melanoma of an autologous tumor-dendritic cell fusion (dendritoma) vaccine with low dose interleukin-2. Cancer Immunol Immunother 2016; 65: 383–392.
193. Slingluff CL, Jr. The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination? Cancer J 2011; 17: 343–350.
194. Nishimura F, Dusak JE, Eguchi J, et al. Adoptive transfer of type 1 CTL mediates effective anti-central nervous system tumor response: critical roles of IFN-inducible protein-10. Cancer Res 2006; 66: 4478–4487.
195. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 2015; 161: 205–214.
196. Chiappinelli KB, Zahnow CA, Ahuja N, et al. Combining epigenetic and immunotherapy to combat cancer. Cancer Res 2016; 76: 1683–1689.
197. Kim K, Skora AD, Li Z, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 2014; 111: 11774–11779.
198. Zheng H, Zhao W, Yan C, et al. HDAC inhibitors enhance T cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin Cancer Res 2016; 22: 4119–4132.
199. van der Vlist M, Kuball J, Radstake TR, et al. Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us? Nat Rev Rheumatol 2016; 12: 593–604.
200. Casey SC, Tong L, Li Y, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 2016; 352: 227–231.
201. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010; 116: 3268–3277.
202. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 2011; 471: 377–381.
203. Twa DD, Chan FC, Ben-Neriah S, et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 2014; 123: 2062–2065.
204. Kataoka K, Shiraishi Y, Takeda Y, et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature 2016; 534: 402–406.