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

Autor: Wei Qiu, Qindong Guo, Xiaofan Guo, Chaochao Wang, Boyan Li, Yanhua Qi, Shaobo Wang, Rongrong Zhao, Xiao Han, Hao Du, Shulin Zhao, Ziwen Pan, Yang Fan, Qingtong Wang, Zijie Gao, Gang Li, Hao Xue
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Journal of Nanobiotechnology, Vol 21, Iss 1, Pp 1-19 (2023)
Druh dokumentu: article
ISSN: 1477-3155
DOI: 10.1186/s12951-023-01997-x
Popis: 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. Graphical abstract
Databáze: Directory of Open Access Journals
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