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Decitabine enhances targeting of AML cells by CD34+ progenitor-derived NK cells in NOD/SCID/IL2Rgnull mice

Jeannette Cany, Mieke W.H. Roeven, Janneke S. Hoogstad-van Evert, Willemijn Hobo, Frans Maas, Rosalia Franco Fernandez, Nicole M.A. Blijlevens, Walter J. van der Velden, Gerwin Huls, Joop H. Jansen, Nicolaas P.M. Schaap and Harry Dolstra

Key points

  • CD34+ progenitor-derived NK cells and hypomethylating agents potently cooperate against AML cells.

  • Decitabine-mediated modulation of CD34-derived NK cell phenotype, function, and trafficking results in enhanced anti-leukemic effect in vivo.

Abstract

Combining NK cell adoptive transfer with hypomethylating agents (HMA) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMA on NK cell functionality are mostly derived from in vitro studies with high non-clinical relevant drug concentrations. Here, we report a comparative study of azacitidine and decitabine in combination with allogeneic NK cells generated from CD34+ hematopoietic stem and progenitor cells (HSPC-NK cells) in in vitro and in vivo AML models. In vitro, low-dose HMA did not impair HSPC-NK cell viability. Furthermore, low-dose decitabine preserved HSPC-NK killing, proliferation and IFN-γ production capacity, while azacitidine diminished their proliferation and reactivity. Importantly, we showed that HMA and HSPC-NK cells can potently cooperate to target AML cell lines and patient AML blasts. In vivo, both agents exerted a significant delay in AML progression in NOD/SCID/IL2Rgnull mice, while the persistence of adoptively transferred HSPC-NK cells was not affected. Infused NK cells showed sustained expression of most activating receptors, up-regulated NKp44 expression and remarkable KIR acquisition. Most importantly, only decitabine potentiated HSPC-NK cell anti-leukemic activity in vivo. Besides up-regulation of NKG2D and DNAM-1 activating ligands on AML cells, decitabine enhanced mRNA expression of inflammatory cytokines, perforin, and TRAIL by HSPC-NK cells. In addition, treatment resulted in increased numbers of HSPC-NK cells in the bone marrow compartment, suggesting that decitabine could positively modulate NK cell activity, trafficking and tumor targeting. These data provide a rationale to explore combination therapy of adoptive HSPC-NK cells and decitabine in AML patients.

  • Submitted June 22, 2017.
  • Accepted November 6, 2017.