Epithelial–Mesenchymal Transition in Human Prostate Cancer Demonstrates Enhanced Immune Evasion Marked by IDO1 Expression

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 ( = 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; log-fold change = 5.1; = 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. 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. .

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

“…Notably, the PFS on the placebo arm was identical to that reported in the pivotal IMPACT study for sipuleucel-T. These positive data align with recent evidence that epithelial-mesenchyme transition (EMT) drives IDO1 expression as part of this key step in metastatic progression of prostate cancer to its deadly castrate-resistant form ( 64 ). Overall, the findings of this randomized phase 2 trial with a placebo control arm strongly encourages further study of indoximod as an immunometabolic adjuvant for prostate cancer treatment.…”

LncRNA KCNQ1OT1 sponges miR-15a to promote immune evasion and malignant progression of prostate cancer via up-regulating PD-L1

“…Cell autonomous behaviors, such as proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), critically drive the malignant growth, the metastatic spread, and the resistance to therapy of PC. In addition, these biological behaviors also link tumor cells with other cell types within the tumor microenvironment to nurture tumor development [5]. One mechanism utilized by tumor cells is through the regulation of programmed death ligand 1 (PD-L1).…”

Overexpression of Indoleamine 2,3-Dioxygenase 1 Promotes Epithelial-Mesenchymal Transition by Activation of the IL-6/STAT3/PD-L1 Pathway in Bladder Cancer

“…Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme that catalyzes the breakdown of tryptophan into kynurenine. High expression levels of IDO1 have been found in various human tumor tissues, including prostate cancer [4], lung cancer [5], and chronic lymphocytic leukemia [6]; therefore, it is believed to play an important role in the development of cancer. In addition, a high IDO expression level in tumor tissues is usually associated with a poor patient prognosis [7].…”