Human Dendritic Cells Mitigate NK-Cell Dysfunction Mediated by Nonselective JAK1/2 Blockade
| Autor: | David J. Chung, James W. Young, Shane A. Curran, Brian C. Betts, Justin A. Shyer, Lillian R. Talbot, Katharine C. Hsu, Erin T. St Angelo, Glenn Heller, Sneh Sharma |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Ruxolitinib Immunology Cell Biology Article Cell Line Immunophenotyping 03 medical and health sciences chemistry.chemical_compound Interferon-gamma medicine STAT5 Transcription Factor Humans Secretion Lymphocyte Count Phosphorylation Protein Kinase Inhibitors STAT5 Cells Cultured Myeloproliferative Disorders Dendritic cell Dendritic Cells Janus Kinase 1 TG101348 Janus Kinase 2 Coculture Techniques Killer Cells Natural 030104 developmental biology medicine.anatomical_structure chemistry Cancer research biology.protein Cytokines Receptors Natural Killer Cell Janus kinase medicine.drug Signal Transduction |
| Zdroj: | Cancer immunology research. 5(1) |
| ISSN: | 2326-6074 |
| Popis: | Janus kinase (JAK) inhibitors have achieved positive responses in myeloproliferative neoplasms, but at the expense of decreased natural killer (NK) cell numbers and compromised function. Selective JAK2 inhibition may also have a role in preventing and treating graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Although JAK inhibitors can impair monocyte-derived dendritic cell (moDC) activation and function and suppress effector T-cell responses, the effects on NK cells and the relevant mechanisms remain undefined. Using common γc cytokines and distinct human dendritic cell (DC) subtypes, we compared the effects of a JAK2-specific (TG101348) with a less selective JAK1/2 (ruxolitinib) inhibitor on NK-cell activation and function. Ruxolitinib treatment completely blocked IL2, IL15, and DC-mediated STAT5 phosphorylation, along with the capacity of NK cells to secrete IFNγ or lyse NK cell–sensitive targets. Only NK-cell proliferation stimulated by moDCs resisted ruxolitinib treatment. In contrast, TG101348 treatment of stimulated NK cells resulted in far less functional compromise. TG101348 completely inhibited only soluble IL15-mediated STAT5 phosphorylation, which Langerhans-type DCs (LCs), presenting membrane-bound IL15 in trans, could salvage. These results demonstrate that ruxolitinib's nonselective inhibition of JAK1/2 results in profound NK-cell dysfunction by blocking downstream pSTAT5, hence providing a persuasive rationale for the development of selective JAK2 inhibitors for immunotherapeutic applications. Cancer Immunol Res; 5(1); 52–60. ©2016 AACR. |
| Databáze: | OpenAIRE |
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