Oncotarget

Research Papers: Immunology:

Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome

Ebba Sohlberg _, Aline Pfefferle, Sandra Andersson, Bettina C. Baumann, Eva Hellström-Lindberg and Karl-Johan Malmberg

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Oncotarget. 2015; 6:34178-34190. https://doi.org/10.18632/oncotarget.6213

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Abstract

Ebba Sohlberg1, Aline Pfefferle1, Sandra Andersson1, Bettina C. Baumann1, Eva Hellström-Lindberg2 and Karl-Johan Malmberg1,3,4

1 Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

2 Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

3 Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway

4 The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Correspondence to:

Karl-Johan Malmberg, email:

Ebba Sohlberg, email:

Keywords: myelodysplastic syndrome, natural killer cell, killer cell immunoglobulin-like receptors, 5-azacytidine, Immunology and Microbiology Section, Immune response, Immunity

Received: June 30, 2015 Accepted: September 12, 2015 Published: October 21, 2015

Abstract

5-azacytidine (5-aza) is a hypomethylating agent approved for the treatment of high-risk myelodysplastic syndrome (MDS). It is assumed to act by demethylating tumor suppressor genes and via direct cytotoxic effects on malignant cells. In vitro treatment with hypomethylating agents has profound effects on the expression of killer-cell immunoglobulin-like (KIR) receptors on natural killer (NK) cells, as these receptors are epigenetically regulated via methylation of the promoters. Here we investigated the influence of 5-aza on the NK-cell repertoire during cytokine-induced proliferation in vitro and homeostatic proliferation in vivo in patients with high-risk MDS. In vitro treatment of NK cells from both healthy donors and MDS patients with low doses of 5-aza led to a significant increase in expression of multiple KIRs, but only in cells that had undergone several rounds of cell division. Proliferating 5-aza exposed NK cells exhibited increased IFN-γ production and degranulation towards tumor target cells. MDS patients had lower proportions of educated KIR-expressing NK cells than healthy controls but after systemic treatment with 5-aza, an increased proportion of Ki-67+ NK cells expressed multiple KIRs suggesting uptake of 5-aza in cycling cells in vivo. Hence, these results suggest that systemic treatment with 5-aza may shape the NK cell repertoire, in particular during homeostatic proliferation, thereby boosting NK cell-mediated recognition of malignant cells.


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