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Erschienen in: Cancer Immunology, Immunotherapy 7/2016

08.12.2015 | Focussed Research Review

Improving cancer immunotherapy with DNA methyltransferase inhibitors

verfasst von: Mohammad H. Saleh, Lei Wang, Michael S. Goldberg

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2016

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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.
Literatur
9.
15.
16.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
17.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
19.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
20.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
21.
Zurück zum Zitat 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 CrossRef 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 CrossRef
22.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
23.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
27.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat 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 CrossRef 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 CrossRef
29.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
30.
Zurück zum Zitat 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 8:2690PubMed 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 8:2690PubMed
33.
Zurück zum Zitat 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 4:7PubMed 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 4:7PubMed
34.
Zurück zum Zitat 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 CrossRef 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 CrossRef
36.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
37.
Zurück zum Zitat 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 14:1178–1189CrossRefPubMedPubMedCentral 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 14:1178–1189CrossRefPubMedPubMedCentral
41.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
42.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
45.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
48.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
50.
Zurück zum Zitat 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 CrossRef 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 CrossRef
51.
52.
Zurück zum Zitat 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 CrossRef 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 CrossRef
54.
Zurück zum Zitat 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 CrossRef 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 CrossRef
55.
Zurück zum Zitat 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 CrossRef 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 CrossRef
56.
Zurück zum Zitat 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 CrossRef 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 CrossRef
58.
Zurück zum Zitat 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 4:2067–2079CrossRefPubMedPubMedCentral 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 4:2067–2079CrossRefPubMedPubMedCentral
59.
Zurück zum Zitat 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 5:587–598CrossRefPubMedPubMedCentral 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 5:587–598CrossRefPubMedPubMedCentral
62.
Zurück zum Zitat 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 50:125–133CrossRefPubMed 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 50:125–133CrossRefPubMed
64.
65.
Zurück zum Zitat 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 CrossRef 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 CrossRef
Metadaten
Titel
Improving cancer immunotherapy with DNA methyltransferase inhibitors
verfasst von
Mohammad H. Saleh
Lei Wang
Michael S. Goldberg
Publikationsdatum
08.12.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 7/2016
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-015-1776-3

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