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

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

doi:10.1002/cti2.1441

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

Clin Transl Immunology. 2023 Feb 25;12(2):e1441. doi: 10.1002/cti2.1441. eCollection 2023.

Authors

Yigeng Cao^{1

2

3}, Jiali Wang^{1

2

3}, Shan Jiang^{1

2}, Mengnan Lyu^{1

2

3}, Fei Zhao^{1

2

3}, Jia Liu^{1

2

3}, Mingyang Wang^{1

2

3}, Xiaolei Pei^{1

2

3}, Weihua Zhai^{1

2

3}, Xiaoming Feng^{1

2}, Sizhou Feng^{1

2

3}, Mingzhe Han^{1

2

3}, Yuanfu Xu^{1

2}, Erlie Jiang^{1

2

3}

Affiliations

¹ State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Tianjin China.
² Tianjin Institutes of Health Science Tianjin China.
³ Hematopoietic Stem Cell Transplantation Center, Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Tianjin China.

Abstract

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.

Keywords: JAK/STAT pathway; ROS; acute graft‐versus‐host disease; myeloid‐derived suppressor cells.