Expression of Indoleamine 2,3-Dioxygenase Induced by IFN-γ and TNF-α as Potential Biomarker of Prostate Cancer Progression

Abstract

Inflammation has been suggested to play an important role in onset and progression of prostate cancer (PCa). Histological analysis of prostatectomy specimens has revealed focal inflammation in early stage lesions of this malignancy. We addressed the role of inflammatory stimuli in the release of PCa-specific, tumor-derived soluble factors (PCa-TDSFs) already reported to be mediators of PCa morbidity, such as indoleamine 2,3-dioxygenase (IDO) and interleukin (IL)-6. Inflammation-driven production and functions of PCa-TDFSs were tested “in vitro” by stimulating established cell lines (CA-HPV-10 and PC3) with IFN-γ or TNF-α. Expression of genes encoding IDO, IL-6, IFN-γ, TNF-α, and their receptors was investigated in tumor tissues of PCa patients undergoing radical prostatectomy, in comparison with benign prostatic hyperplasia (BPH) specimens. IFN-γ and TNF-α-treatment resulted in the induction of IDO and IL-6 gene expression and release in established cell lines, suggesting that the elicitation of PCa-TDSFs by these cytokines might contribute to progression of cancer into an untreatable phenotype. An analysis based on timing of biochemical recurrence revealed the prognostic value of IDO but not IL-6 gene expression in predicting recurrence-free survival in patients (RFS) with PCa. In addition, a urine-based mRNA biomarker study revealed the diagnostic potential of IDO gene expression in urines of men at risk of PCa development.

Targeting the IDO1 pathway in cancer: from bench to bedside

“…In addition, IDO1 plays a key role in promoting tumor neovascularization by modulating the expression of interferon-γ (IFN-γ) and interleukin-6 (IL-6) [ 10 , 11 ]. In prostate cancer cells, IFN-γ and TNF-α-treatment induce IDO1 and IL-6 gene expression [ 12 ]. Furthermore, IDO1 is involved in the formation of resistance to immune checkpoint inhibitors [ 13 ], and the combination of an IDO1 inhibitor with checkpoint inhibitors represents an alternative strategy in cancer immunotherapy [ 14 ].…”

Effect of Indoleamine 2,3 Dioxygenase Inhibitor on the Cytotoxic Activity of Tumour-infiltrating Lymphocytes

“…The third target is PD-L1, a ligand of PD-1, whose expression is decreased in the inflammatory state (not expressed at basal state). It has been confirmed that IDO inhibitor stimulates tryptophan degradation activity in a dose-dependent manner (12).…”

Treatment Combinations with DNA Vaccines for the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC)

“…IDO gene expression has been detected in human prostate cancers [ 131 ], however, IDO activity is more typically measured by serum kynurenine and tryptophan levels, yielding a (kyn:trp) ratio. This ratio has been debated as a biomarker of prostate cancer detection or progression [ 132 , 133 ]. In recent studies, we assessed serum kyn:trp ratios from patients with different stages of prostate cancer and found that IDO activity increased with stage of disease [ 10 ].…”