Abstract Cancer invasion and metastasis are driven by epithelial–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 patients with prostate cancer. We performed laser capture microdissection 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 immunostainings 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 immunosuppressive 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 patients with prostate cancer. Significance: These findings demonstrate EMT is linked to an immunosuppressive environment in clinical prostate cancer, suggesting that patients with prostate cancer can potentially benefit from combinatorial drug therapy. Cancer Res; 78(16); 4671–9. ©2018 AACR.