Breast cancer-derived exosomes transmit lncRNA SNHG16 to induce CD73+γδ1 Treg cells

Abstract

AbstractγδT cells have been reported to exert immunosuppressive functions in multiple solid malignant diseases, but their immunosuppressive functional subpopulation in breast cancer (BC) is still undetermined. Here, we collected 40 paired BC and normal tissue samples from Chinese patients for analysis. First, we showed that γδT1 cells comprise the majority of CD3+ T cells in BC; next, we found that CD73+γδT1 cells were the predominant regulatory T-cell (Treg) population in BC, and that their prevalence in peripheral blood was also related to tumour burden. In addition, CD73+γδT1 cells exert an immunosuppressive effect via adenosine generation. We also found that BC could modulate CD73 expression on γδT cells in a non-contact manner. The microarray analysis and functional experiments indicated that breast tumour cell-derived exosomes (TDEs) could transmit lncRNA SNHG16, which upregulates CD73 expression, to Vδ1 T cells. Regarding the mechanism, SNHG16 served as a ceRNA by sponging miR-16–5p, which led to the derepression of its target gene SMAD5 and resulted in potentiation of the TGF-β1/SMAD5 pathway to upregulate CD73 expression in Vδ1 T cells. Our results showed that the BC-derived exosomal SNHG16/miR-16–5p/SMAD5-regulatory axis potentiates TGF-β1/SMAD5 pathway activation, thus inducing CD73 expression in Vδ1 T cells. Our results first identify the significance of CD73+Vδ1 Tregs in BC, and therapy targeting this subpopulation or blocking TDEs might have potential for BC treatment in the future.

ceRNA Network Development and Tumour-infiltrating Immune Cell Analysis in Metastatic Breast Cancer of Bone

“…Due to the frequent occurrence of bone metastasis in patients with advanced breast cancer, the pathogenesis and clinical management of bone metastasis are important and challenging topics in basic research and clinical practice. The ceRNAs network, including mRNA, miRNA, and lncRNA, and immune cells that in ltrate the tumour may be critical to further understand this phenomenon [12][13][14][15]. We observed that tumour samples with bone metastasis had signi cantly altered proportions of in ltrating cells compared with breast cancer without bone metastasis.…”

“…Lncrna is a type of ncRNA with over 200 nucleotides, which has nothing to do with protein-coding [12][13][14][15][16]. New evidence suggests that lncRNA imbalance occurs frequently in many malignant tumours and are vital for carcinogenesis through post-transcriptional regulation and epigenetic modi cation [17,18].…”

“…Recently, an increasing number of studies show that aberrant lncrnas expression leads to the development of many kinds of malignant tumours, including breast cancer [12][13][14][15][16][17][18]. As a kind of lncrnas, dlx6-as1 is believed to be carcinogenic by regulating the progression of renal cell carcinoma, liver cell carcinoma, glioma, pancreatic cancer and lung adenocarcinoma [19][20][21][22][23][24][25][26].…”

Long noncoding RNA: a dazzling dancer in tumor immune microenvironment

“…7 a) [ 95 ]. Infiltrating CD73 + γδ1Tregs exert a key immunosuppressive effect via adenosine generation in the breast TME [ 96 ]. Breast cancer-derived exosomal lncRNA SNHG16 stimulates the activation of the TGF-β1/SMAD5 pathway via mediating miR-16-5p and drives the conversion of γδ1 Tregs into the CD73 + immunosuppressive subtype (Fig.…”

“…Breast cancer-derived exosomal lncRNA SNHG16 stimulates the activation of the TGF-β1/SMAD5 pathway via mediating miR-16-5p and drives the conversion of γδ1 Tregs into the CD73 + immunosuppressive subtype (Fig. 7 a; Table 1 ) [ 96 ].

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