Journal Article

JAK1/2 inhibitor ruxolitinib promotes the expansion and suppressive action of polymorphonuclear myeloid‐derived suppressor cells via the JAK/STAT and ROS‐MAPK/NF‐κB signalling pathways in acute graft‐versus‐host disease

Wang, Mingyang, Cao, Yigeng, Jiang, Erlie, Lyu, Mengnan, Feng, Xiaoming, Pei, Xiaolei, Zhai, Weihua, Zhao, Fei, Feng, Sizhou, Wang, Jiali, Xu, Yuanfu, Han, Mingzhe, Jiang, Shan, Liu, Jia

2023

Overview

Objectives Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, demonstrates efficacy for treating steroid‐resistant acute graft‐versus‐host disease (SR‐aGVHD) following allogeneic stem cell transplantation (allo‐HSCT). Myeloid‐derived suppressor cells (MDSCs) have a protective effect on aGVHD via suppressing T cell function. However, the precise features and mechanism of JAK inhibitor‐mediated immune modulation on MDSCs subsets remain poorly understood. Methods A total of 74 SR‐aGVHD patients treated with allo‐HSCT and ruxolitinib were enrolled in the present study. The alterations of MDSC and regulatory T cell (Treg) populations were monitored during ruxolitinib treatment in responders and nonresponders. A mouse model of aGVHD was used to evaluate the immunosuppressive activity of MDSCs and related signalling pathways in response to ruxolitinib administration in vivo and in vitro. Results Patients with SR‐aGVHD who received ruxolitinib treatment achieved satisfactory outcomes. Elevation proportions of MDSCs before treatment, especially polymorphonuclear‐MDSCs (PMN‐MDSCs) were better to reflect the response to ruxolitinib than those in Tregs. In the mouse model of aGVHD, the administration of ruxolitinib resulted in the expansion and functional enhancement of PMN‐MDSCs and the effects could be partially reversed by an anti‐Gr‐1 antibody in vivo. Ruxolitinib treatment significantly elevated the suppressive function of PMN‐MDSCs through reactive oxygen species (ROS) production by Nox2 upregulation as well as bypassing the activated MAPK/NF‐κB signalling pathway. Additionally, ex vivo experiments demonstrated that ruxolitinib prevented the differentiation of mature myeloid cells and promoted the accumulation of MDSCs by inhibiting STAT5. Conclusions Ruxolitinib enhances PMN‐MDSCs functions through JAK/STAT and ROS‐MAPK/NF‐κB signalling pathways. Monitoring frequencies and functions of MDSCs can help evaluate treatment responses to ruxolitinib. Our results provide rationale for molecular modification of myeloid‐derived suppressor cells to augment the efficacy of ruxolitinib in patients with acute graft‐versus‐host disease, which may be applicable to other pathologies including autoimmunity, chronic inflammation and cancer.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: acute graft‐versus‐host disease / Cell differentiation / Correlation analysis / CYBB protein / Cytomegalovirus / Fungal infections / Graft versus host disease / Graft-versus-host reaction / Granulocytes / Immunomodulation / Immunosuppressive agents / Inhibitor drugs / JAK/STAT pathway / Janus kinase / Lymphocytes / Lymphocytes T / MAP kinase / Medical prognosis / Medical treatment / Myeloid cells / myeloid‐derived suppressor cells / NF-κB protein / Original / Patients / Reactive oxygen species / Response rates / ROS / Signal transduction / Stat5 protein / Stem cell transplantation / Suppressor cells / Tumor necrosis factor-TNF / Viral infections