2. Academic Validation
  3. Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop

Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop

  • J Nanobiotechnology. 2023 Jul 22;21(1):233. doi: 10.1186/s12951-023-01997-x.
Wei Qiu 1 2,  Qindong Guo 1 2,  Xiaofan Guo 1 2 3,  Chaochao Wang 1 2 4,  Boyan Li 1 2,  Yanhua Qi 1 2,  Shaobo Wang 1 2,  Rongrong Zhao 1 2,  Xiao Han 1 2 5,  Hao Du 6,  Shulin Zhao 1 2,  Ziwen Pan 1 2,  Yang Fan 1 2,  Qingtong Wang 1 2,  Zijie Gao 1 2,  Gang Li 7 8,  Hao Xue 9 10
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road, Jinan, Shandong, 250012, China.
  • 2 Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China.
  • 3 Department of Neurology, Loma Linda University Health, Loma Linda, CA, 92350, USA.
  • 4 Department of Neurosurgery, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, China.
  • 5 Department of Neurosurgery, Jinan Children's Hospital, Jinan, Shandong, China.
  • 6 Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.
  • 7 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road, Jinan, Shandong, 250012, China. dr.ligang@sdu.edu.cn.
  • 8 Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China. dr.ligang@sdu.edu.cn.
  • 9 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road, Jinan, Shandong, 250012, China. xuehao@sdu.edu.cn.
  • 10 Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China. xuehao@sdu.edu.cn.
PMID: 37481646 DOI: 10.1186/s12951-023-01997-x
Abstract

Background: The immunosuppressive microenvironment in glioma induces immunotherapy resistance and is associated with poor prognosis. Glioma-associated mesenchymal stem cells (GA-MSCs) play an important role in the formation of the immunosuppressive microenvironment, but the mechanism is still not clear.

Results: We found that GA-MSCs promoted the expression of CD73, an ectonucleotidase that drives immunosuppressive microenvironment maintenance by generating adenosine, on myeloid-derived suppressor cells (MDSCs) through immunosuppressive exosomal miR-21 signaling. This process was similar to the immunosuppressive signaling mediated by glioma exosomal miR-21 but more intense. Further study showed that the miR-21/SP1/DNMT1 positive feedback loop in MSCs triggered by glioma exosomal CD44 upregulated MSC exosomal miR-21 expression, amplifying the glioma exosomal immunosuppressive signal. Modified dendritic cell-derived exosomes (Dex) carrying miR-21 inhibitors could target GA-MSCs and reduce CD73 expression on MDSCs, synergizing with anti-PD-1 monoclonal antibody (mAb).

Conclusions: Overall, this work reveals the critical role of MSCs in the glioma microenvironment as signal multipliers to enhance immunosuppressive signaling of glioma exosomes, and disrupting the positive feedback loop in MSCs with modified Dex could improve PD-1 blockade therapy.

Keywords

Anti-PD-1 therapy; Exosomes; Glioma; Mesenchymal stem cells; Myeloid-derived suppressor cells; miR-21.

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