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

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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Acknowledgments

This work was supported in part by the grants from Associazione Italiana per la Ricerca sul Cancro (IG 11746 to MM and MFAG 9195 to LS), Fondazione Monte dei Paschi di Siena (SC), Harry J. Lloyd Charitable Trust (MM), Istituto Superiore di Sanità (MM), Istituto Toscano Tumori (MM), and Regione Toscana “Regional Health Research Program 2009″ (MM).

Conflict of interest

The authors declare no potential conflict of interest.

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Authors and Affiliations

  1. Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Aviano, Italy

    Sandra Coral, Francesca Colizzi, Elisabetta Fratta & Luca Sigalotti

  2. Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Strada delle Scotte 14, 53100, Siena, Italy

    Giulia Parisi, Hugues J. M. G. Nicolay, Riccardo Danielli, Alessia Covre & Michele Maio

  3. Astex Pharmaceuticals, Inc., Dublin, CA, USA

    Pietro Taverna

Authors
  1. Sandra Coral
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  2. Giulia Parisi
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  3. Hugues J. M. G. Nicolay
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  4. Francesca Colizzi
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  9. Luca Sigalotti
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  10. Michele Maio
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Correspondence to Michele Maio.

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Coral, S., Parisi, G., Nicolay, H.J.M.G. et al. Immunomodulatory activity of SGI-110, a 5-aza-2′-deoxycytidine-containing demethylating dinucleotide. Cancer Immunol Immunother 62, 605–614 (2013). https://doi.org/10.1007/s00262-012-1365-7

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  • DOI: https://doi.org/10.1007/s00262-012-1365-7

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