Repression of GSK3 restores NK cell cytotoxicity in AML patients

Reshmi Parameswaran (), Parameswaran Ramakrishnan, Stephen A. Moreton, Zhiqiang Xia, Yongchun Hou, Dean A. Lee, Kalpana Gupta, Marcos deLima, Rose C. Beck and David N. Wald ()
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Reshmi Parameswaran: Case Western Reserve University
Parameswaran Ramakrishnan: Case Western Reserve University
Stephen A. Moreton: Case Western Reserve University
Zhiqiang Xia: Invenio Therapeutics
Yongchun Hou: Case Western Reserve University
Dean A. Lee: The University of Texas Health Sciences Center, MD Anderson Cancer Center
Kalpana Gupta: Case Western Reserve University
Marcos deLima: University Hospitals Case Medical Center
Rose C. Beck: University Hospitals Case Medical Center
David N. Wald: Case Western Reserve University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11154

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