Research Papers:

Maintenance therapy with histamine plus IL-2 induces a striking expansion of two CD56bright NK cell subpopulations in patients with acute myeloid leukemia and supports their activation

Angélica Cuapio _, Mirte Post, Sabine Cerny-Reiterer, Karoline V. Gleixner, Gabriele Stefanzl, Jose Basilio, Susanne Herndlhofer, Wolfgang R. Sperr, Nicolaas H.C. Brons, Emilio Casanova, Jacques Zimmer, Peter Valent and Erhard Hofer

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Oncotarget. 2016; 7:46466-46481. https://doi.org/10.18632/oncotarget.10191

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Angélica Cuapio1,*, Mirte Post1,*, Sabine Cerny-Reiterer2,3, Karoline V. Gleixner2,3, Gabriele Stefanzl2, Jose Basilio1, Susanne Herndlhofer2,3, Wolfgang R. Sperr2,3, Nicolaas H.C. Brons4, Emilio Casanova5,6, Jacques Zimmer7, Peter Valent2,3, Erhard Hofer1

1Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria

2Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria

3Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria

4National Core Facility Cytometry, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg

5Ludwig Boltzmann Institute of Cancer Research, Vienna, Austria

6Institute of Pharmacology, Center of Physiology and Pharmacology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

7Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg

*These authors have contributed equally to this work

Correspondence to:

Angélica Cuapio, email: [email protected]; [email protected]

Keywords: natural killer cells, CD56bright, CD56dim, histamine, IL-2

Received: August 25, 2015     Accepted: May 28, 2016     Published: June 21, 2016


Histamine dihydrochloride (HDC) plus IL-2 has been proposed as a novel maintenance-immunotherapy in acute myeloid leukemia (AML). We analyzed the immunophenotype and function of natural killer (NK) cells in blood of AML patients treated after chemotherapy with HDC plus IL-2. The treatment caused a striking expansion of CD56brightCD16neg and CD56brightCD16low NK cell subpopulations. A reduced NK cell fraction recovered and high proportions of cells expressed the activating receptors NKG2D, NKp30, and NKp46. Concomitantly, KIR-expressing NK cells were reduced and NK cells with inhibitory NKG2A/CD94 receptors increased beyond normal levels. In addition, the immunotherapy-induced NK cells exhibited high capacity to produce IFN-γ and to degranulate. Furthermore, we provide evidence from subsequent in vitro studies that this is caused in part by direct effects of IL-2 on the CD56bright cells. IL-2 specifically induced proliferation of both CD56bright subpopulations, but not of CD56dim cells. It further preserved the expression of activating receptors and the capacity to produce IFN-γ and to degranulate. These data suggest that therapy with HDC plus IL-2 supports the reconstitution of a deficient NK cell fraction through the specific amplification of CD56bright NK cells giving rise to a functional NK cell compartment with high potential to combat leukemic disease.

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