title: JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms.
abstract: Ruxolitinib is a small-molecule inhibitor of the JAK kinases, which has been approved for the treatment of myelofibrosis, a rare myeloproliferative neoplasm (MPN), but clinical trials are also being conducted in inflammatory-driven solid tumors. Increased infection rates have been reported in ruxolitinib-treated patients, and natural killer (NK) cells are immune effector cells known to eliminate both virus-infected and malignant cells. On this basis, we sought to compare the effects of JAK inhibition on human NK cells in a cohort of 28 MPN patients with or without ruxolitinib treatment and 24 healthy individuals. NK cell analyses included cell frequency, receptor expression, proliferation, immune synapse formation, and cytokine signaling. We found a reduction in NK cell numbers in ruxolitinib-treated patients that was linked to the appearance of clinically relevant infections. This reduction was likely due to impaired maturation of NK cells, as reflected by an increased ratio in immature to mature NK cells. Notably, the endogenous functional defect of NK cells in MPN was further aggravated by ruxolitinib treatment. In vitro data paralleled these in vivo results, showing a reduction in cytokine-induced NK cell activation. Further, reduced killing activity was associated with an impaired capacity to form lytic synapses with NK target cells. Taken together, our findings offer compelling evidence that ruxolitinib impairs NK cell function in MPN patients, offering an explanation for increased infection rates and possible long-term side effects associated with ruxolitinib treatment.
authors.affiliation: Medical Clinic, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schönberg
authors.affiliation: Medical Clinic, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.
authors.forename: Janna
authors.initials: J
authors.lastname: Rudolph
authors.affiliation: Medical Clinic, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Vonnahme
authors.affiliation: Medical Clinic, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Parampalli Yajnanarayana
authors.affiliation: Medical Clinic, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cornez
authors.affiliation: Institute for Transplantation Diagnostics and Cell Therapeutics, University Clinic Düsseldorf, Düsseldorf, Germany.
authors.forename: Maryam
authors.initials: M
authors.lastname: Hejazi
authors.affiliation: Institute for Transplantation Diagnostics and Cell Therapeutics, University Clinic Düsseldorf, Düsseldorf, Germany.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Manser
authors.affiliation: Institute for Transplantation Diagnostics and Cell Therapeutics, University Clinic Düsseldorf, Düsseldorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Uhrberg
authors.affiliation: ZAHO, Bonn, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Verbeek
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Medical Clinic, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Medical Clinic, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.
authors.forename: Annkristin
authors.initials: A
authors.lastname: Heine
authors.affiliation: Medical Clinic, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany. dominik.wolf@ukb.uni-bonn.de.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019046:Bone Marrow Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009570:Nitriles; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; C507933:JAK3 protein, human; D053616:Janus Kinase 3