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

Prostate cancer is a heterogeneous disease in terms of pathological growth patterns, molecular aberrations and clinical outcome. It is currently graded according to the Gleason Scoring system, but analysis of individual growth patterns can provide additional information on tumour cell biology and clinical behaviour.

Typical Gleason Scores range from 6-10. The higher the Gleason Score, the more likely that the cancer will grow and spread quickly. Scores of 6 or less describe cancer cells that look similar to normal cells and suggest that the cancer is likely to grow slowly. A score of 7 suggests and intermediate risk for aggressive cancer and scores of 8 or higher describe cancers that are likely to spread more rapidly: these cancers are often referred to as poorly differentiated or high grade.

Cancer invasion and metastasis are driven by epithelial-to-mesenchymal transition (EMT). It is characterised by the acquisition of a mesenchymal-like phenotype by epithelial cells. Epithelial cells that undergo EMT in vitro become spindle shaped and up-regulate mesenchymal markers such as vimentin, fibronectin, N- and OB-cadherin combined with suppression of epithelial markers such as keratins and E-cadherin. In clinical prostate cancer, N-cadherin is rare in localised low-grade tumours, but it is increased in high-grade progressive disease. Concomitant N-cadherin up-regulation and E-cadherin down-regulation, also referred to as cadherin switching, has been found to be the most reliable marker for EMT in prostate cancer patient samples. However, the exact mechanisms and regulatory pathways that are involved in cadherin switching and EMT in clinical prostate cancer is currently unclear.

In a recent study, Kolijn et al performed laser capture micro-dissection of matched N-cadherin-positive and -negative prostate cancer areas from patient samples followed by RNA sequencing to determine the molecular and cellular mechanisms associated with N-cadherin expression in prostate cancer patients.

Kolijn et al found that:

N-cadherin expression was significantly associated with altered immune regulatory pathways including a profound (log2 fold change 5.1) up-regulation of indoleamine 2, 3-dioxygenase (IDO1).

Fluorescent immune staining of patient samples confirmed expression of IDO1 protein and also its metabolite kynurenine in primarily N-cadherin-positive areas.

Enhanced enzymatic activity of IDO1 in tissues led to cadherin switching, (down-regulated expression of E-cadherin and up-regulated expression of N-cadherin) in prostate cancer cell lines.

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+).

EMT is a biological process involved in tumour invasion, resistance to chemotherapy and metastasis. Although expression of N-cadherin is considered a hallmark of EMT in clinical prostate cancer, it is still unclear what mechanisms drive EMT in cancer patients. IDO1 is an enzyme involved in the degradation of tryptophan into kynurenines, which drive T cell differentiation towards an immunosuppressive state through local depletion of tryptophan.

Here, Kolijn et al show that EMT, characterised by N-cadherin expression in ill-formed tumour glands, was related to local enrichment of immunosuppressive molecules such as IDO1 in clinical prostate cancer. The concomitant enrichment of CD4+/FOXP3+ T regulatory cells and reduction of intraepithelial CD8+ cytotoxic T cells, indicated an intimate interaction between EMT as marked by N-cadherin expression and local evasion of an effective anti-tumour CD8 T cell response in prostate cancer. Together these findings reveal an important link between EMT and immune evasion in prostate cancer patients.

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Epistem will be reporting on the development of its prostate cancer model at the AACR in March.

Epistem is your ideal partner for cancer drug discovery using our range of in vitro and in vivo cancer models. We have orthotopic, in-life imaging oncology models validated for a number of cancer types with more in development. We also offer in vitro cytotoxicity testing in cell lines and cancer stem cell assays.

Supporting all of our services we have GCLP-compliant Histology/IHC and gene expression laboratories. We have extensive experience analysing RNA from low input samples including “RNA-friendly” laser capture microdissection of specific cell types such as TILs. We have recently expanded our gene expression services with the purchase of a NextSeq NGS machine.

Kolijn et al., 2018. Epithelial-Mesenchymal Transition in Human Prostate Cancer Demonstrates Enhanced Immune Evasion Marked by IDO1 Expression. Cancer Res August 14 2018 78 (16) 4671-4679

DOI: 10.1158/0008-5472.CAN-17-3752

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