PMID- 27923824 OWN - NLM STAT- MEDLINE DCOM- 20171122 LR - 20181202 IS - 2326-6074 (Electronic) IS - 2326-6066 (Print) IS - 2326-6066 (Linking) VI - 5 IP - 1 DP - 2017 Jan TI - Human Dendritic Cells Mitigate NK-Cell Dysfunction Mediated by Nonselective JAK1/2 Blockade. PG - 52-60 LID - 10.1158/2326-6066.CIR-16-0233 [doi] AB - 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 gamma(c) 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 IFNgamma 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. (c)2016 AACR. CI - (c)2016 American Association for Cancer Research. FAU - Curran, Shane A AU - Curran SA AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. FAU - Shyer, Justin A AU - Shyer JA AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. FAU - St Angelo, Erin T AU - St Angelo ET AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. FAU - Talbot, Lillian R AU - Talbot LR AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. FAU - Sharma, Sneh AU - Sharma S AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. FAU - Chung, David J AU - Chung DJ AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. AD - Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York. AD - Myeloma Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York. AD - Weill Cornell Medical College, New York, New York. AD - The Rockefeller University, New York, New York. FAU - Heller, Glenn AU - Heller G AD - Biostatistics Service, Department of Biostatistics and Epidemiology, New York, New York. FAU - Hsu, Katharine C AU - Hsu KC AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. AD - Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York. AD - Weill Cornell Medical College, New York, New York. FAU - Betts, Brian C AU - Betts BC AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. AD - Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York. FAU - Young, James W AU - Young JW AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. youngj@mskcc.org. AD - Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, MSKCC, New York, New York. AD - Weill Cornell Medical College, New York, New York. AD - The Rockefeller University, New York, New York. LA - eng GR - P01 CA023766/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R01 CA083070/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20161206 PL - United States TA - Cancer Immunol Res JT - Cancer immunology research JID - 101614637 RN - 0 (Cytokines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Receptors, Natural Killer Cell) RN - 0 (STAT5 Transcription Factor) RN - 82115-62-6 (Interferon-gamma) RN - EC 2.7.10.2 (Janus Kinase 1) RN - EC 2.7.10.2 (Janus Kinase 2) SB - IM MH - Cell Line MH - Cells, Cultured MH - Coculture Techniques MH - Cytokines/metabolism MH - Dendritic Cells/*immunology/*metabolism MH - Humans MH - Immunophenotyping MH - Interferon-gamma/metabolism MH - Janus Kinase 1/*antagonists & inhibitors MH - Janus Kinase 2/*antagonists & inhibitors MH - Killer Cells, Natural/*immunology/*metabolism MH - Lymphocyte Count MH - Myeloproliferative Disorders/drug therapy/immunology/metabolism/pathology MH - Phosphorylation MH - Protein Kinase Inhibitors/*pharmacology MH - Receptors, Natural Killer Cell/metabolism MH - STAT5 Transcription Factor/metabolism MH - Signal Transduction/drug effects PMC - PMC5335862 MID - NIHMS835427 COIS- Conflict of interest: The authors declare no potential conflicts of interest. EDAT- 2016/12/08 06:00 MHDA- 2017/11/29 06:00 PMCR- 2017/07/01 CRDT- 2016/12/08 06:00 PHST- 2016/09/08 00:00 [received] PHST- 2016/11/11 00:00 [revised] PHST- 2016/11/19 00:00 [accepted] PHST- 2016/12/08 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] PHST- 2016/12/08 06:00 [entrez] PHST- 2017/07/01 00:00 [pmc-release] AID - 2326-6066.CIR-16-0233 [pii] AID - 10.1158/2326-6066.CIR-16-0233 [doi] PST - ppublish SO - Cancer Immunol Res. 2017 Jan;5(1):52-60. doi: 10.1158/2326-6066.CIR-16-0233. Epub 2016 Dec 6.