Peritumoral indoleamine 2,3-dioxygenase expression in melanoma: an early marker of resistance to immune control?

ABSTRACT

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an emerging immunomodulating factor in cancer. IDO expression in tumour-negative sentinel lymph nodes (SLNs) of patients with melanoma has a negative prognostic value. OBJECTIVES: To analyse the expression pattern of IDO and associated immunological changes in corresponding primary melanomas (PMs), SLNs and metastases. METHODS: In 120 patients with melanoma, PMs with corresponding SLNs (n = 85) and metastases (n = 18) were analysed by immunohistochemical staining for IDO and FoxP3. Tumour-infiltrating lymphocytes (TILs) were scored. IDO expression in stimulated peripheral blood mononuclear cells (PBMCs) was analysed in 27 patients. RESULTS: IDO expression in the sentinel node strongly correlated with endothelial IDO expression in the peritumoral stroma of the corresponding primary (P < 0·001) and metastatic melanoma (P < 0·05). Sentinel IDO positivity was inversely correlated with CD8+ lymphocytes (P = 0·01) and TILs (P = 0·05) in PM. Both IDO expression in the sentinel (P < 0·01) and the PM (P = 0·04) had a negative prognostic effect on overall survival, independent of Breslow thickness, sex, age, ulceration and sentinel invasion. IDO expression by PBMCs after stimulation with cytotoxic T-lymphocyte antigen 4 was not correlated with sentinel IDO expression but tended to correlate with disease stage (P = 0·04). CONCLUSIONS: Endothelial IDO expression is highly consistent in primary, sentinel and metastatic tissues of patients with melanoma, indicating that immune suppression in melanoma is determined very early in the disease course. This supports that IDO expression in melanoma is a marker of antitumour immune response with an independent prognostic value.