Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts

Pragya Srivastava, Benjamin E. Paluch, Junko Matsuzaki, Smitha R. James, Golda Collamat-Lai, Pietro Taverna, Adam R. Karpf, Elizabeth A. Griffiths

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

We aimed to determine the effect of SGI-110 on methylation and expression of the cancer testis antigens (CTAs) NYESO-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 CD8C T-cells. We also tested the impact of combined SGI-110 and NYESO-1-specific CD8C 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 CD8C 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 CD8C T-cells. Sequential SGI-110 and antigen-specific CD8C 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.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalEpigenetics
Volume10
Issue number3
DOIs
StatePublished - Mar 20 2015

Keywords

  • Cancer germline genes
  • Cancer testis antigens
  • DNA methylation
  • DNA methyltransferase inhibitors
  • Epigenetics
  • Epithelial ovarian cancer
  • Immune modulation
  • SGI-110

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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