Repression of GSK3 restores NK cell cytotoxicity in AML patients.

Reshmi Parameswaran,Marcos Delima,Parameswaran Ramakrishnan,David N Wald,Dean A Lee,Stephen A Moreton,Yongchun Hou,Kalpana Gupta,Zhiqiang Xia,Rose C Beck

doi:10.1038/ncomms11154

Abstract

Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. The exact reasons for this dysfunction are not fully understood. Here we show that the glycogen synthase kinase beta (GSK3β) expression is elevated in AML-NK cells. Interestingly, GSK3 overexpression in normal NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK3 inactivation enhances their cytotoxic activity. Mechanistic studies reveal that the increased cytotoxic activity correlates with an increase in AML-NK cell conjugates. GSK3 inhibition promotes the conjugate formation by upregulating LFA expression on NK cells and by inducing ICAM-1 expression on AML cells. The latter is mediated by increased NF-κB activation in response to TNF-α production by NK cells. Finally, GSK3-inhibited NK cells show significant efficacy in human AML mouse models. Overall, our work provides mechanistic insights into the AML-NK dysfunction and a potential NK cell therapy strategy.

Highlights

Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity
In an effort to understand the dysregulation of NK cells in AML patients, we found that glycogen synthase kinase beta (GSK3-b) protein levels are upregulated in NK cells from AML patients as compared with normal donors
As GSK3 protein expression is known to be elevated in cancer cells[19,20,21,22,23,24,25,26], we tested whether GSK3 protein expression is altered in NK cells from AML patients

Summary

Introduction

Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. Engagement of lymphocyte functionassociated antigen 1 (LFA-1) by its ligand, intercellular adhesion molecule-1 (ICAM-1), on target cells is one such interaction resulting in the stable adhesion of NK cells to their target cells and is sufficient to induce the polarization of lytic granules in resting NK cells[7]. Another important step is cytokine production by NK cells including interferon-g (IFN-g) and tumour necrosis factor-a (TNF-a)[8]. Specific signalling alterations leading to these functional changes are not clear

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Results

Conclusion