2. Academic Validation
  3. mTOR Signaling Regulates the Development and Therapeutic Efficacy of PMN-MDSCs in Acute GVHD

mTOR Signaling Regulates the Development and Therapeutic Efficacy of PMN-MDSCs in Acute GVHD

  • Front Cell Dev Biol. 2021 Dec 23;9:741911. doi: 10.3389/fcell.2021.741911.
Xiaoqing Li 1 2 3 4,  Yixue Li 1 2 3 4,  Qinru Yu 1 2 3 4,  Lin Xu 1 2 3 4,  Shan Fu 1 2 3 4,  Cong Wei 1 2 3 4,  Limengmeng Wang 1 2 3 4,  Yi Luo 1 2 3 4,  Jimin Shi 1 2 3 4,  Pengxu Qian 2 3 4,  He Huang 1 2 3 4,  Yu Lin 1 2 3 4
Affiliations

Affiliations

  • 1 Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
  • 3 Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.
  • 4 Institute of Hematology, Zhejiang University, Hangzhou, China.
PMID: 35004668 DOI: 10.3389/fcell.2021.741911
Abstract

Myeloid-derived suppressor cells (MDSCs) represent a population of heterogeneous myeloid cells, which are characterized by their remarkable ability to suppress T cells and natural killer cells. MDSCs have been proven to play a positive role in protecting acute graft-versus-host disease (aGVHD). Here, we aimed to describe the mechanism behind how mTOR signaling regulates MDSCs' generation and explore its prophylactic and therapeutic potential in aGVHD. Reducing mTOR expression retains myeloid cells with immature characteristics and promotes polymorphonuclear MDSC (PMN-MDSC) immunosuppressive function through STAT3-C/EBPβ pathway. Prophylactic transfusion of mTORKO PMN-MDSCs could alleviate aGVHD while maintaining the graft-versus-leukemia (GVL) effect, which could downregulate the Th1/Th2 ratio, decrease serum proinflammatory cytokines, and increase the proportion of regulatory T cells (Tregs) in aGVHD models at the early stage after transplantation. Moreover, transfusion therapy could promote the reconstruction and function of donor-derived PMN-MDSCs. Not only the percentage and the absolute number of donor-derived PMN-MDSCs significantly increased but also the immunosuppressive ability was much more robust compared to other groups. Altogether, these findings indicated that mTOR is an intrinsic regulator for PMN-MDSCs' differentiation and immunosuppressive function. Together, mTORKO PMN-MDSC transfusion can play a protective role in alleviating cytokine storm at the initial stage and promoting the quantitative and functional recoveries of donor-derived PMN-MDSCs in aGVHD.

Keywords

GVL effect; acute GVHD; allogeneic HSCT; mTOR; polymorphonuclear MDSCs.

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