JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms
| Autor: | Tim H. Brümmendorf, Peter Brossart, Kathrin Schönberg, Dominik Wolf, Sowmya Parampalli Yajnanarayana, Walter Verbeek, Steffen Koschmieder, Angela R. Manser, Janna Rudolph, Maria Vonnahme, Maryam Hejazi, Annkristin Heine, Markus Uhrberg, Isabelle Cornez |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Cancer Research Ruxolitinib Receptor expression medicine.medical_treatment Cell Biology Immunological synapse Neoplasms Nitriles medicine Humans Myelofibrosis Myeloproliferative neoplasm Aged Cell Proliferation Aged 80 and over Kinase Janus Kinase 3 Middle Aged medicine.disease Killer Cells Natural Pyrimidines Cytokine medicine.anatomical_structure Oncology Primary Myelofibrosis Immunology Pyrazoles Female Bone Marrow Neoplasms Signal Transduction medicine.drug |
| Zdroj: | Cancer Research. 75:2187-2199 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-14-3198 |
| Popis: | 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. Cancer Res; 75(11); 2187–99. ©2015 AACR. |
| Databáze: | OpenAIRE |
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