title: Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts.
abstract: We aimed to determine the effect of SGI-110 on methylation and expression of the cancer testis antigens (CTAs) NY-ESO-1 and MAGE-A in epithelial ovarian cancer (EOC) cells in vitro and in vivo and to establish the impact of SGI-110 on expression of major histocompatibility (MHC) class I and Intracellular Adhesion Molecule 1 (ICAM-1) on EOC cells, and on recognition of EOC cells by NY-ESO-1-specific CD8+ T-cells. We also tested the impact of combined SGI-110 and NY-ESO-1-specific CD8+ T-cells on tumor growth and/or murine survival in a xenograft setting. EOC cells were treated with SGI-110 in vitro at various concentrations and as tumor xenografts with 3 distinct dose schedules. Effects on global methylation (using LINE-1), NY-ESO-1 and MAGE-A methylation, mRNA, and protein expression were determined and compared to controls. SGI-110 treated EOC cells were evaluated for expression of immune-modulatory genes using flow cytometry, and were co-cultured with NY-ESO-1 specific T-cell clones to determine immune recognition. In vivo administration of SGI-110 and CD8+ T-cells was performed to determine anti-tumor effects on EOC xenografts. SGI-110 treatment induced hypomethylation and CTA gene expression in a dose dependent manner both in vitro and in vivo, at levels generally superior to azacitidine or decitabine. SGI-110 enhanced the expression of MHC I and ICAM-1, and enhanced recognition of EOC cells by NY-ESO-1-specific CD8+ T-cells. Sequential SGI-110 and antigen-specific CD8+ cell treatment restricted EOC tumor growth and enhanced survival in a xenograft setting. SGI-110 is an effective hypomethylating agent and immune modulator and, thus, an attractive candidate for combination with CTA-directed vaccines in EOC.
authors: a Department of Medicine; Roswell Park Cancer Institute ; Buffalo NY USA.
authors: Pragya
authors: P
authors: Srivastava
authors: Benjamin E
authors: BE
authors: Paluch
authors: Junko
authors: J
authors: Matsuzaki
authors: Smitha R
authors: SR
authors: James
authors: Golda
authors: G
authors: Collamat-Lai
authors: Pietro
authors: P
authors: Taverna
authors: Adam R
authors: AR
authors: Karpf
authors: Elizabeth A
authors: EA
authors: Griffiths
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013601:T-Lymphocytes
chemical_list: D000951:Antigens, Neoplasm; D004791:Enzyme Inhibitors; C580831:guadecitabine; D008780:Methyltransferases; D001374:Azacitidine
keywords: AZA, Azacitidine (5-azacytidine); CTA, Cancer-testis antigen or cancer-germline antigen; CTAG1B, Cancer/testis antigen 1B; DAC, Decitabine (5-aza-2′-deoxycitidine); DNA methylation; DNA methyltransferase inhibitors; DNA, Deoxyribonucleic acid; DNMTi, DNA methyltransferase inhibitor; EOC, Epithelial ovarian cancer; HLA, Human leukocyte antigen; ICAM-1, Intracellular Adhesion Molecule 1; LINE-1, Long interspersed nuclear element-1; MAGE-A, Melanoma antigen family A; MHC, Major histocompatibility complex; NY-ESO-1, New york esophageal squamous cell carcinoma 1; RNA, Ribonucleic acid; SGI-110; cancer germline genes; cancer testis antigens; epigenetics; epithelial ovarian cancer; immune modulation