Human dendritic cells mitigate NK-cell dysfunction mediated by nonselective JAK1/2 blockade

Shane A. Curran, Justin A. Shyer, Erin T. St Angelo, Lillian R. Talbot, Sneh Sharma, David J. Chung, Glenn Heller, Katharine C. Hsu, Brian C. Betts, James W. Young

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)52-60
Number of pages9
JournalCancer Immunology Research
Volume5
Issue number1
DOIs
StatePublished - Jan 2017

Bibliographical note

Funding Information:
This study was financially supported by grants P01-CA23766 (K.C. Hsu, G. Heller, J.W. Young), R01-CA83070 (J.W. Young), and Cancer Center Support GrantP30-CA08748 to Memorial Sloan Kettering Cancer Center, from the NCI, NIH; and the Long Island Sound Chapter of Swim Across America (J.W. Young).

Publisher Copyright:
© 2016 AACR.

Fingerprint

Dive into the research topics of 'Human dendritic cells mitigate NK-cell dysfunction mediated by nonselective JAK1/2 blockade'. Together they form a unique fingerprint.

Cite this