title: Human Dendritic Cells Mitigate NK-Cell Dysfunction Mediated by Nonselective JAK1/2 Blockade.
abstract: 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 γccytokines 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.
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Curran
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Shyer
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.
authors.forename: Erin T
authors.initials: ET
authors.lastname: St Angelo
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.
authors.forename: Lillian R
authors.initials: LR
authors.lastname: Talbot
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.
authors.forename: Sneh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.|Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York.|Myeloma Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York.|Weill Cornell Medical College, New York, New York.|The Rockefeller University, New York, New York.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chung
authors.affiliation: Biostatistics Service, Department of Biostatistics and Epidemiology, New York, New York.
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.|Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Hsu
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.|Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Betts
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. youngj@mskcc.org.|Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York.|Weill Cornell Medical College, New York, New York.|The Rockefeller University, New York, New York.
authors.forename: James W
authors.initials: JW
authors.lastname: Young
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D018655:Lymphocyte Count; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D055607:Receptors, Natural Killer Cell; D050799:STAT5 Transcription Factor; D007371:Interferon-gamma; D053613:Janus Kinase 1; D053614:Janus Kinase 2