<p>Exosomal miRNA-107 induces myeloid-derived suppressor cell expansion in gastric cancer</p>

Abstract

Background: Myeloid-derived suppressor cells (MDSCs) promote immunosuppression in the tumor microenvironment, support tumor growth and survival, and may contribute to immunotherapy resistance. Recent studies showed that tumor-derived exosomes (TDEs) can induce MDSCs accumulation and expansion, the mechanisms of which are largely unknown. Methods: The morphologies and sizes of the exosomes was observed by using a JEM-1400 transmission electron microscope. MicroRNA(miR)-107 and ARG1 , DICER1 , PTEN , PI3K , AKT , mTOR , and NF-kB mRNAs were quantified by quantitative reverse tanscription PCR. Dual-Luciferase Reports Assay were used to examine the expression of genes which was targeted by miR-107. The expression of proteins were analyzed by using western blot. Results: MiR-107 was not only overexpressed in gastric cancer cells but also enriched in their secreted TDEs. Also, these miR-107 enriched TDEs could be taken up by HLA-DR - CD33 + MDSCs, where miR-107 was able to target and suppress expression of DICER1 and PTEN genes. Dampened DICER1 expression supported expansion of MDSCs , while decreased PTEN led to activation of the PI3K pathway, resulting in increased ARG1 expression. Furthemore, gastric cancer-derived miR-107 TDEs, when dosed intravenously into mice, were also capable of inducing expansion of CD11b + Gr1 +/high MDSCs in mouse peripheral blood and altering expression of DICER1 , PTEN , ARG1 , and NOS2 in the MDSCs. Conclusions: Our findings demonstrate for the first time that gastric cancer-secreted exosomes are able to deliver miR-107 to the host MDSCs where they induce their expansion and activition by targeting DICER1 and PTEN genes, thereby may provide novel cancer therapeutics target for gastric cancer.

Jianpi Huayu Decoction Attenuates the Immunosuppressive Status of H22 Hepatocellular Carcinoma-Bearing Mice: By Targeting Myeloid-Derived Suppressor Cells

“…Besides, JHD could affect the apoptosis, differentiation and immunosuppressive ability of MDSCs, possibly through multiple molecule signaling pathways, e.g. NF-kB (Flores et al, 2017), STAT-3 (Guha et al, 2019), HMGB1, AMPK (Salminen et al, 2019), microRNAs (Ren et al, 2019). However, we suspected that JHD plays multiple roles by regulating STAT-3, which was involved in processes such as cell transformation, expansion and activation of MDSCs (Panni et al, 2014;Pan et al, 2016).…”

The role of cancer-derived microRNAs in cancer immune escape

“…Immunosuppressive [125] miR-24-3p NPC Immunosuppressive [126] miR-891a NPC Immunosuppressive [126] miR-106a-5p NPC Immunosuppressive [126] miR-20a-5p NPC Immunosuppressive [126] miR-1908 NPC Immunosuppressive [126] TAMs miR-222-3p EOC Immunosuppressive [127] miR-940 EOC Immunosuppressive [128] miR-21-3p EOC Immunosuppressive [129] miR-125b-5p EOC Immunosuppressive [129] miR-181d-5p EOC Immunosuppressive [129] miR-21 Head and neck cancer Immunosuppressive [130] miR-1246 Colon cancer Immunosuppressive [131] miR-16 Breast cancer Immunostimulatory [132] MDSCs miR-107 Gastric cancer Immunosuppressive [133] miR-21 OSCC Immunosuppressive [134] miR-21 Glioma Immunosuppressive [135] miR-10a Glioma Immunosuppressive [135] miR-29a Glioma Immunosuppressive [136] miR-92a Glioma Immunosuppressive [136] miR-155 CLL Immunosuppressive [137] CAFs miR-27a Gastric cancer Immunosuppressive [138] miR-1247-3p HCC Immunosuppressive [139] miR-21 HCC Immunosuppressive [140] NPC nasopharyngeal carcinoma, TAM tumor-associated macrophage, EOC epithelial ovarian cancer, MDSC myeloid-derived suppressor cell, OSCC oral squamous cell carcinoma, CLL chronic lymphocytic leukemia, CAF cancer-associated fibroblast, HCC hepatocellular carcinoma M2-like phenotype and suppressing the expression of M1 phenotype-associated markers [130]. Similarly, Cooks et al observed that cancer cells harboring TP53 mutation could reprogram neighboring TAMs into pro-tumor state via secreting miR-1246-enriched exosomes [131].…”

“…Accumulating evidence has indicated that cancerderived exosomal miRNAs are capable of regulating the abundance and function of MDSCs [144]. Ren et al reported that gastric cancer cells enhanced the expansion and activity of MDSCs by delivering miRNA-107enriched exosomes [133]. Similarly, in the condition of hypoxia, glioma secreted exosomal miR-29a and miR-92a which enhanced the proliferation and function of MDSCs via targeting Hbp1 as well as Prkar1a [136].…”

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

“…More recently, the microRNA cargo of TEVs was deeply investigated and associated with the TEV-mediated MDSC expansion. Gastric cancer EVs delivered miR-107 to MDSCs, targeting DICER1 and PTEN, thus contributing to cell expansion and activation [28]. Further, the in vivo injection of miR-107 to mice promoted the accumulation of MDSC in the peripheral blood [28].…”

“…Gastric cancer EVs delivered miR-107 to MDSCs, targeting DICER1 and PTEN, thus contributing to cell expansion and activation [28]. Further, the in vivo injection of miR-107 to mice promoted the accumulation of MDSC in the peripheral blood [28]. The MDSC-mediated immunosuppressive environment was largely described also in glioma [29]; recently, glioma-EVs were described as responsible for this event [30,31].…”