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

Abstract

Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) 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 HMAs did not impair viability of HSPC-NK cells. Furthermore, low-dose DAC preserved HSPC-NK killing, proliferation, and interferon gamma production capacity, whereas AZA diminished their proliferation and reactivity. Importantly, we showed HMAs and HSPC-NK cells could potently work together to target AML cell lines and patient AML blasts. In vivo, both agents exerted a significant delay in AML progression in NOD/SCID/IL2Rg mice, but the persistence of adoptively transferred HSPC-NK cells was not affected. Infused NK cells showed sustained expression of most activating receptors, upregulated NKp44 expression, and remarkable killer cell immunoglobulin-like receptor acquisition. Most importantly, only DAC potentiated HSPC-NK cell anti-leukemic activity in vivo. Besides upregulation of NKG2D- and DNAM-1-activating ligands on AML cells, DAC enhanced messenger RNA 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 DAC 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 DAC in patients with AML.

DNT Cell-based Immunotherapy: Progress and Applications

“…Xu H et al [65] found that DNTs combined with gemcitabine had a better inhibitory effect on transplanted pancreatic tumors in mice. It was also reported that doxorubicin and bortezomib could upregulate the expression of NKG2D and DNAM-1 ligands on melanoma cells [108][109][110][111], promoting more effective DNT killing of tumor cells.…”

Immune checkpoint molecules in acute myeloid leukaemia: managing the double‐edged sword

“…Thereby, they can improve AML recognition and promote priming of tumour-reactive T cells (Cruijsen et al, 2016;Srivastava et al, 2016). Recently, we also observed that HMA, specifically decitabine, potentiate AML-reactive NK cell responses (Cany et al, 2017). HMA may further modulate tumour immunogenicity by up-regulation of immune stimulatory molecules, including CD80, CD86, ULBP and MIC-A (Zimmer et al, 2008;Yang et al, 2014).…”

Pharmacological targeting of natural killer cells for cancer immunotherapy

“…The DNA methyltransferase inhibitor azacitidine/5‐azacytidine is a chemical analog of nucleoside cytidine used to treat AML and myelodysplastic syndromes. Decitabine was reported to increase NK‐cell effector function, 41 in addition to their maturation and infiltration into tumor site 42 . The mechanism of action of decitabine on NK cells can be explained by the epigenetic induction of gene expression of cytokines and cytotoxic molecules such as perforin or TRAIL 42 …”