Immune evasion by TGFβ-induced miR-183 repression of MICA/B expression in human lung tumor cells

Abstract

Immune escape is a hallmark of cancer. In human lung cancer, we have identified a unique microRNA (miR)-based pathway employed by tumor cells to repress detection by immune cells via the NKG2D-MICA/B receptor-ligand system. MICA/B is readily induced by cell transformation and serves as a danger signal and ligand to alert NK and activated CD8 + T cells. However, immunohistochemical analysis indicated that human lung adenocarcinoma and squamous cell carcinoma specimens express little MICA/B while high levels of miR-183 were detected in both tumor types in a TCGA database. Human lung tumor cell lines confirmed the reverse relationship in expression of MICA/B and miR-183. Importantly, a miR-183 binding site was identified on the 3ʹuntranslated region (UTR) of both MICA and MICB, suggesting its role in MICA/B regulation. Luciferase reporter constructs bearing the 3ʹUTR of MICA or MICB in 293 cells supported the function of miR-183 in repressing MICA/B expression. Additionally, anti-sense miR-183 transfection into H1355 or H1299 tumor cells caused the upregulation of MICA/B. Abundant miR-183 expression in tumor cells was traced to transforming growth factor-beta (TGFβ), as evidenced by antisense TGFβ transfection into H1355 or H1299 tumor cells which subsequently lost miR-183 expression accompanied by MICA/B upregulation. Most significantly, anti-sense miR-183 transfected tumor cells became more sensitive to lysis by activated CD8 + T cells that express high levels of NKG2D. Thus, high miR-183 triggered by TGFβ expressed in lung tumor cells can target MICA/B expression to circumvent detection by NKG2D on immune cells.

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

“…Moreover, the inhibition of MHC class I chain-related protein A/B (MICA/B) expression and NKG2D NK-cell receptor ligands is another mechanism of immune suppression targeting NK cells cytotoxicity. A recent report has identified a novel miRNA, miR-183 that targets MIC A/B in lung cancer [90]. Similar modulation has been reported for miR-10b in BCC [91], miR-20a in ovarian cancer [92], and miR-25-93-106b, miR-20a, miR-93, miR-106b and miR-17-92 cluster in HCC [93,94].…”

NK Cell Function Regulation by TGF-β-Induced Epigenetic Mechanisms

“…Interestingly, NK cells infiltrating lung cancers were shown to have a diminished DAP12 expression (43). Recently, a mechanism of immune evasion has been described in human lung cancer cells (44). TGF-β appears to act simultaneously on NK cells and tumor cells via miR-183, with the result to inhibit the NK cells' anti-tumor activity by down-regulating DAP12, in NK cells, and NKG2D ligands (MICA and MICB), in cancer cells.…”

MiRNAs and LncRNAs: Dual Roles in TGF-β Signaling-Regulated Metastasis in Lung Cancer

“…CASC11 can augment TGF-β1 to promote lung cancer cell stemness [139]. TGF-β-induced miR-183 can down-regulate MICA and MICB to make NSCLC cells escape from immune attacks mediated by circulating immune cells (i.e., natural killer (NK) cells and CD8+ T cells) expressing NKG2D [52]. Additionally, in the NSCLC microenvironment, tumor-derived TGF-β can also increase miR-183, which can decrease DNAX activating protein 12 kDa (DAP12) (a protein required for NK cell cytotoxicity functions), ultimately inhibiting tumor-infiltrating NK cell activities to promote immunosuppression [140], while miRNAs and lncRNAs can also exhibit opposite effects on lung cancer metastasis.…”

“…PD-L1 can bind to programmed cell death protein-1 (PD-1), expressed on activated T cells and other immune cells, ultimately suppressing anti-tumor immunity in NSCLC [51]. In H1355 and H1299 cells, TGF-β can induce miR-183 to down-regulate major histocompatibility complex class I chain-related A (MICA) and MICB expression, which can help H1355 and H1299 cells evade immune detection mediated by the circulating immune cells that express NKG2D (the transmembrane glycoproteins that can recognize MICA and MICB), thereby driving immune evasion ( Figure 2) [52]. lymphatic endothelial cells (LECs), subsequently promoting cell transmigration across LEC monolayers [48].…”