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-vs-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 monocyte-derived DCs (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.

Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation

“…In comparison, ruxolitinib inhibits JAK1 and JAK2 equally (4). Ruxolitinib is known to suppress STAT5 phosphorylation in human T cells and NK cells via JAK1 inhibition (15,17). Others and we show that ruxolitinib, as opposed to pacritinib, significantly impairs human CTL function (15), although this is not observed among murine T cells in vivo (Fig.…”

“…Ruxolitinib suppresses host-reactive T cells in mice (4,(12)(13)(14) and humans (4,11). Although not observed in murine transplant studies (4,(12)(13)(14), ruxolitinib reduces the quantity of human Tregs (15) and natural killer (NK) cells (16,17). Therefore, targeting JAK2 has the potential to prevent GVHD without conceding JAK1-mediated functions provided by donor lymphocytes.…”

Ruxolitinib Might Be an Effective Hormone Reduction and Replacement Drug in Children With Secondary Hemophagocytic Lymphohistiocytosis 

“…34 Ruxolitinib also reversibly improved the killing and degranulation of NK cells and ameliorated organ damage in HLH animal models. 16,[35][36] In 2016, Das et al used lymphocytic choriomeningitis virus to infect perforinde cient mice and construct a model of secondary HLH. A large dose of ruxolitinib (90 mg/kg) not only improved the disease symptoms and decreased cytokine levels in HLH model mice, but also increased the survival rates in mice.…”

Reprint of: Emerging Therapeutics for the Control of Chronic Graft-versus-Host Disease

“…Ruxolitinib inhibits JAK1 and JAK2 with similar potency, is US Food and Drug Administration (FDA) approved for the treatment of intermediate to high-risk myelofibrosis [58], and has shown promising efficacy in treating steroid-refractory GVHD [36,37]. Myelofibrosis patients treated with ruxolitinib do exhibit significantly reduced numbers of circulating Th1, Th17, Tregs, and NK cells [46][47][48]. The loss of human Th1 and Th17 cells is likely driven primarily by JAK2 inhibition [38,46,59], whereas Tregs and NK cells are susceptible to JAK1 blockade and impaired STAT5 signal transduction [46][47][48].…”

“…Myelofibrosis patients treated with ruxolitinib do exhibit significantly reduced numbers of circulating Th1, Th17, Tregs, and NK cells [46][47][48]. The loss of human Th1 and Th17 cells is likely driven primarily by JAK2 inhibition [38,46,59], whereas Tregs and NK cells are susceptible to JAK1 blockade and impaired STAT5 signal transduction [46][47][48]. The broad immune suppression by ruxolitinib may increase the risk of opportunistic infections, including reports of cytomegalovirus retinitis, mycobacterial infections, and Cryptococcus meningitis [49].…”