Mesenchymal Stem Cells, As Glioma Exosomal Immunosuppressive Signal Multipliers, Enhance MDSCs Immunosuppressive Activity Through the MiR-21/SP1/DNMT1 Positive Feedback Loop

Overview

Journal J Nanobiotechnology

Publisher Biomed Central

Specialty Biotechnology

Date 2023 Jul 22

PMID 37481646

Authors

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

Affiliations

Soon will be listed here.

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.

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