Concentration-Dependent Decitabine Effects on Primary NK Cells Viability, Phenotype, and Function in the Absence of Obvious NK Cells Proliferation-Original Article.

Xiang Li,Yong You,Xianghong Wang,Yaohui Wu,Min Zhang,Li Wang,Sisi Cai

doi:10.3389/fphar.2021.755662

Abstract

Acute myeloid leukemia (AML) cells can evade innate immune killing by modulating natural killer (NK) cells receptors and their cognate ligands in tumor cells, thus it may be possible to restore proper expression of immune receptors or ligands with immune sensitive drugs. Decitabine, as a hypomethylation agent, was approved for the treatment of AML and myelodysplastic syndrome. While clinical responses were contributed by epigenetic effects and the induction of cancer cell apoptosis, decitabine also has immune-mediated anti-tumor effects. After exposure to various concentration of decitabine for 24 h, the primary NK cells (AML-NK cells) cytotoxicity and receptor expression (NKG2D and NKp46) displayed parabola-shaped response, while U-shaped response was seen in cytokine release (IFN-γ and IL-10), and these effects were regulated by ERK and STAT3 phosphorylation level. Furthermore, AML-NK cells function displayed different response when the competitive MEK and STAT3 inhibitors applied respectively. Thus, we could conclude that the different dose of decitabine makes various effects on AML-NK cells function and receptors expression.

Highlights

Acute myeloid leukemia (AML), is caused by hyperproliferation and/or impaired differentiation of myeloid precursor cells, mostly affecting older individuals at a median age of 67 years (Estey, 2007; Oran and Weisdorf, 2012)
The viability of natural killer (NK) cells decreased after exposure to decitabine for 24 h (Figure 1A) and it was induced by direct cell death (dead cells rate rose sharply as the concentration of decitabine increased (Figure 1B)
There was no prominent difference when compared the AML-NK cells cytotoxicity among various sub-group, which implied that the AML-NK cells cytotoxicity was independent of FAB subtype, patient age, gender, and risk stratification (Figures 2C–F)

Summary

Introduction

Acute myeloid leukemia (AML), is caused by hyperproliferation and/or impaired differentiation of myeloid precursor cells, mostly affecting older individuals at a median age of 67 years (Estey, 2007; Oran and Weisdorf, 2012). Age and cytogenetics are important prognostic factors for patients with AML, and AML patients with a TP53 mutation or who are classified at high-risk groups respond poorly to traditional chemotherapy and had reduced overall survival relative to non-adverse AML patients. Allogeneic hematopoietic stem cell transplantation represents a potentially curative treatment for AML, but It does not eliminate the risk of relapse completely and it is counter-indicated in many elderly patients due to comorbidities or poor performance status. Sex Age (year) Diagnosis Blast cells (%) FAB subtypes Cytogenetic M1 M2 M5 F M M4 M

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