Epithelial-mesenchymal transition in human prostate cancer demonstrates enhanced immune evasion marked by IDO1 expression

Cancer invasion and metastasis are driven by epithelial-to-mesenchymal transition (EMT), yet the exact mechanisms that account for EMT in clinical prostate cancer are not fully understood. Expression of N-cadherin is considered a hallmark of EMT in clinical prostate cancer. In this study, we determined the molecular mechanisms associated with N-cadherin expression in prostate cancer patients. We performed laser capture micro-dissection of matched N-cadherin-positive and -negative prostate cancer areas from patient samples (n=8) followed by RNA sequencing. N-cadherin expression was significantly associated with an immune regulatory signature including profound upregulation of indoleamine 2,3-dioxygenase (IDO1) (log2 fold change=5.1; p=2.98E-04). Fluorescent immune stainings of patient samples confirmed expression of IDO1 protein and also its metabolite kynurenine in primarily N-cadherin-positive areas. N-cadherin-positive areas also exhibited a local decrease of intraepithelial cytotoxic (CD8+) T cells and an increase of immune suppressive regulatory T cells (CD4+/FoxP3+). In conclusion, EMT in clinical prostate cancer is accompanied by upregulated expression of IDO1 and an increased number of regulatory T cells. These data indicate that EMT, which is an important step in tumor progression, can be protected from effective immune control in prostate cancer patients.

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