Natural Killer Cell Subpopulations and Inhibitory Receptor Dynamics in Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Vlad Andrei Cianga,Mohamad Cherry,Lydia Campos Catafal,Cristina Rusu,Denis Guyotat,Emmanuelle Tavernier,Carmen Mariana Aanei,Mariana Pavel Tanasa,Petru Cianga,Phillipe Collet

doi:10.3389/fimmu.2021.665541

Abstract

Natural killer (NK) cells are key innate immunity effectors that play a major role in malignant cell destruction. Based on expression patterns of CD16, CD56, CD57, and CD94, three distinct NK cell maturation stages have been described, which differ in terms of cytokine secretion, tissue migration, and the ability to kill target cells. Our study addressed NK cell maturation in bone marrow under three conditions: a normal developmental environment, during pre-leukemic state (myelodysplastic syndrome, MDS), and during leukemic transformation (acute myeloblastic leukemia, AML). In this study, we used a new tool to perform multicolor flow cytometry data analysis, based on principal component analysis, which allowed the unsupervised, accurate discrimination of immature, mature, and hypermature NK subpopulations. An impaired NK/T cell distribution was observed in the MDS bone marrow microenvironment compared with the normal and AML settings, and a phenotypic shift from the mature to the immature state was observed in NK cells under both the MDS and AML conditions. Furthermore, an impaired NK cell antitumor response, resulting in changes in NK cell receptor expression (CD159a, CD158a, CD158b, and CD158e1), was observed under MDS and AML conditions compared with the normal condition. The results of this study provide evidence for the failure of this arm of the immune response during the pathogenesis of myeloid malignancies. NK cell subpopulations display a heterogeneous and discordant dynamic on the spectrum between normal and pathological conditions. MDS does not appear to be a simple, intermediate stage but rather serves as a decisive step for the mounting of an efficient or ineffective immune response, leading to either the removal of the tumor cells or to malignancy.

Highlights

Natural killer (NK) cells are particular and important components of the immune system, with a major role in the clearance of damaged, virally infected, and tumor cells [1, 2]
The Automatic Population Separator (APS) facilitated the classification of NK events across these three subpopulations of NK cells, those belonging to the CD56bright CD94hi CD16− CD57− subset, which is the least well represented out of the three, and could be under- or overestimated by a biased manual analysis
As other research groups have stressed, the unsupervised identification of NK subsets, based on the simultaneous evaluation of the CD16/CD56/CD57/CD94 set of markers, and automatic gating is more accurate than identification methods using only one or an insufficient number of markers combined with manual interpretation [36]

Summary

Introduction

Natural killer (NK) cells are particular and important components of the immune system, with a major role in the clearance of damaged, virally infected, and tumor cells [1, 2]. They achieve this goal with the help of a highly diverse repertoire of germline-encoded activating and inhibitory receptors that allow NKs to recognize and target cells that lack or downregulate the expression of major histocompatibility complex (MHC) class I molecules [3]. The expression of CD57, a marker of highly differentiated NK cells, has been correlated with a higher cytotoxic potential and long lasting memory, a feature shared with cells that participate in adaptive immunity [12,13,14]

Methods

Results

Conclusion