Indoleamine 2,3-Dioxygenase Expression in Primary Cutaneous Melanoma Correlates with Breslow Thickness and Is of Significant Prognostic Value for Progression-Free Survival

Abstract

The enzyme indoleamine 2,3-dioxygenase (IDO) is emerging as a facilitator of cancer development through its effects on cancer-associated inflammation. Recent studies report a significant improvement of the response rates in melanoma patients to PD-1 antibodies when IDO inhibitors were added to the regimen. Data on IDO expression in primary human melanomas are, however, incomplete and conflicting. Here, we show that the level of IDO expression in primary human melanoma cells significantly correlates with Breslow thickness (P = 0.003), the presence of tumor-infiltrating lymphocytes (P = 0.029), and the intensity of the peritumoral inflammatory infiltrate (P = 0.001). The expression of IDO in melanoma cells predicted independently of Breslow thickness and tumor stage (P = 0.04). We further show that CD11c dendritic cells and CD68 macrophages in the microenvironment of melanomas express IDO. The level of IDO expression in antigen-presenting cells correlated positively to peritumoral inflammation (P = 0.001) but not to tumor-infiltrating lymphocytes. Significant negative correlation with progression-free survival was found for patients for whom antigen-presenting cells were very strongly IDO positive. These results suggest that IDO induction within melanoma cells may directly reflect tumor progression, whereas IDO in antigen-presenting cells may determine immune surveillance with impact on local and systemic tolerance.

Variable indoleamine 2,3‐dioxygenase expression in acral/mucosal melanoma and its possible link to immunotherapy

“…Interestingly, our data showed that the frequency of the IDO expression in tumors was lower in acral and mucosal melanomas than the reported frequency in cutaneous melanomas . The genetic differences between acral and mucosal melanomas and cutaneous melanomas may contribute to the IDO expression levels in tumors and in the peritumoral stroma.…”

“…There are conflicting reports regarding the relevance of IDO as a biomarker. A recent study demonstrated that the IDO expression in cutaneous melanoma was correlated with shorter PFS . Another study found that endothelial expression of IDO was correlated with shorter overall survival .…”

“…The images were captured with an automated slide scanner, Nanozoomer (Hamamatsu Photonics). In the previous reports, IDO− was defined as IDO negative, IDO+ as IDO staining in <25% of tumor or antigen‐presenting cells, IDO++ as IDO staining in 25%‐50% and IDO+++ as IDO staining in >50% . Because there was no case matching IDO++ in our study, we modified the criteria as follows: IDO− as IDO negative, IDO+ as IDO staining in <25% of tumor or peritumoral mononuclear inflammatory cells and IDO++ as ≥25% (Figure A‐C).…”

“…IDO is expressed in tumor cells, dendritic cells, macrophages and endothelial cells in the tumor microenvironment . IDO is expressed in both tumor cells and immune cells in melanomas . A positive correlation between the high expression of IDO and clinical response to anti–CTLA‐4 therapy in melanoma has been reported .…”

Mechanism and prognostic value of indoleamine 2,3‐dioxygenase 1 expressed in hepatocellular carcinoma

“…In contrast, in breast carcinoma, early stage cervical cancer, and melanoma, IDO1 expression is accompany the host antitumor immune response, and it tends to positively correlate with survival . However, in another study, the high inductive IDO1 expression in primary melanoma negatively affected progression‐free survival . Under the heterogeneity of tumor gene mutations and the tumor microenvironment, both constitutive and inducible IDO1 expression can co‐exist regulated by tumor intrinsic and extrinsic mechanisms, reflecting either the absence or presence of antitumor immunity in specific tumor microenvironments.…”