Researchers detected the mechanisms through which tumor-derived exosomal miR-185-5p downregulates T cell activity and leads to poor prognosis in patients with intrahepatic cholangiocarcinoma (iCCA), as published in Hepatology. This finding suggests that miR-185-5p could be useful as a new biomarker for disease progression and prediction of poor prognosis in iCCA.

The team of researchers from China noticed that exosomal miR-185-5p activity was upregulated in iCCA cells compared to primary human intrahepatic biliary epithelial cells, hypothesizing a potential role in the physiopathology of iCCA. The effects of this microRNA involve inhibiting the expression of phosphatase and tensin homologue (PTEN), which in turn favors programmed death-ligand 1 (PD-L1) activity, among other molecules.

The researchers obtained fresh iCCA cells, adjacent nontumor tissues, and peripheral blood samples from 154 patients with iCCA who underwent surgical resection to perform immunohistochemistry assays with the macrophages extracted from each tissue. The results revealed that macrophages in iCCA tumors had significantly higher levels of PD-L1 than those in nonmalignant liver cells and nontumor tissues, including peripheral blood.


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The role of PD-L1 as an immunosuppressive molecule was analyzed, revealing decreased T cell proliferation and interferon-gamma production in iCCA tissues rich in PD-L1 macrophages. Although the presence of macrophages has been previously associated with poor survival rates in various tumors, to demonstrate that miR-185-5p was responsible for the T cell downregulation secondary to PD-L1 activity, iCCA cells were transfected with miR-185-5p inhibitors, resulting in a significant decrease in PD-L1.

Furthermore, the opposite effect was achieved by transfecting macrophages with miR-185-5p mimics. Also, higher miR-185-5p levels correlated with greater tumor size and lymph node involvement. The assessment of pre- and postoperative plasma miR-185-5p levels showed a marked reduction after surgery, suggesting that iCCA tumor cells may be responsible.

“Moreover, high level of plasma exosomal miR-183-5p predicts a poor prognosis of [iCCA] patients after curative resection,” the authors concluded. “Based on this finding, the strategies of [iCCA] treatments could be developed through interfering the specific interactions of miR-183-5p/PTEN/AKT/PD-L1 signaling pathway in future.”

Reference

Luo C, Xin H, Zhou Z, et al. Tumor‐derived exosomes induce immunosuppressive macrophages to foster intrahepatic cholangiocarcinoma progression. Hepatology. Published online February 2, 2022. doi:10.1002/hep.32387