Immunomodulatory activity of SGI-110, a 5-aza-2-deoxycytidine-containing demethylating dinucleotide

Sandra Coral, Giulia Parisi, Hugues J M G Nicolay, Francesca Colizzi, Riccardo Danielli, Elisabetta Fratta, Alessia Covre, Pietro Taverna, Luca Sigalotti, Michele Maio

Research output: Contribution to journalArticle

Abstract

Purpose: Pharmacologic DNA hypomethylation holds strong promises in cancer immunotherapy due to its immunomodulatory activity on neoplastic cells. Searching for more efficient DNA hypomethylating agents to be utilized to design novel immunotherapeutic strategies in cancer, we investigated the immunomodulatory properties of the new DNA hypomethylating agent SGI-110, that is resistant to in vivo inactivation by cytidine deaminase. Experimental design: Cutaneous melanoma, mesothelioma, renal cell carcinoma, and sarcoma cells were treated in vitro with SGI-110. RT-PCR, quantitative RT-PCR, quantitative methylation-specific PCR, and flow cytometric analyses were performed to investigate changes induced by SGI-110 in the constitutive immune profile of cancer cells. The recognition by gp100-specific CTL of gp100-positive melanoma cells, treated or not with SGI-110, was tested by LDH release assays. Results: SGI-110 induced/up-regulated the expression of investigated cancer/testis antigens (CTA) (i.e., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A10, GAGE 1-2, GAGE 1-6, NY-ESO-1, and SSX 1-5) in all cancer cell lines studied, both at mRNA and at protein levels. Quantitative methylation-specific PCR analyses identified a hypomethylation of MAGE-A1 and NY-ESO-1 promoters in SGI-110-treated neoplastic cells, demonstrating a direct role of pharmacologic DNA demethylation in CTA induction. SGI-110 also up-regulated the expression of HLA class I antigens and of ICAM-1, resulting in an improved recognition of cancer cells by gp100-specific CTL. Conclusions: Our findings show that SGI-110 is a highly attractive therapeutic agent to comprehensively increase immunogenicity and immune recognition of neoplastic cells, and provide the scientific rationale for its clinical development to design novel chemo-immunotherapeutic approaches in cancer patients.

Original languageEnglish
Pages (from-to)605-614
Number of pages10
JournalCancer Immunology, Immunotherapy
Volume62
Issue number3
DOIs
Publication statusPublished - Mar 2013

Keywords

  • Cancer
  • DNA hypomethylating agent
  • Epigenetics
  • Immunotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

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  • Cite this

    Coral, S., Parisi, G., Nicolay, H. J. M. G., Colizzi, F., Danielli, R., Fratta, E., Covre, A., Taverna, P., Sigalotti, L., & Maio, M. (2013). Immunomodulatory activity of SGI-110, a 5-aza-2-deoxycytidine-containing demethylating dinucleotide. Cancer Immunology, Immunotherapy, 62(3), 605-614. https://doi.org/10.1007/s00262-012-1365-7