Inter- and intra-patient heterogeneity of indoleamine 2,3-dioxygenase expression in primary and metastatic melanoma cells and the tumor microenvironment.

AIMS: Indoleamine 2,3-dioxygenase (IDO), an immunomodulatory enzyme, facilitates immune escape by tumors and promotes tumor progression. IDO inhibitors with and without additional anti-PD-1 therapy have been evaluated in recent and ongoing melanoma clinical trials, but IDO expression in melanoma tumors and therefore its potential role as a predictive biomarker remains unknown. This study sought to evaluate IDO expression in immunotherapy-naïve metastatic melanoma patients in order to determine patterns of expression in corresponding primary melanomas, locoregional metastases and distant metastases.

METHODS AND RESULTS: Here, we evaluated IDO expression using immunohistochemistry in 99 melanoma tumor samples from 43 immunotherapy-naïve patients with metastatic melanoma to determine patterns of expression in primary melanomas (n=29), locoregional metastases (n=36) and distant metastases (n=34). 37% of patients demonstrated tumor IDO expression in at least one specimen. 12/35 patients (34%) with longitudinal specimens (i.e. two or more separate specimens from different disease stages in the same patient) displayed heterogeneous IDO staining between samples. Tumor IDO expression positively correlated with TIL score as well as the number of IDO-expressing mononuclear cells in the primary melanoma (P<0.0001 and P=0.0011, respectively) and nodal metastases (P=0.049 and P=0.037, respectively), but not in distant metastases. Furthermore, tumor IDO expression correlated positively with PD-L1 expression by melanoma cells across all specimens (P=0.0073).

CONCLUSIONS: Therefore, whilst assessment of tumor IDO expression warrants evaluation in melanoma patient cohorts treated with IDO inhibitors dosed at levels proven to inhibit the target by pharmacodynamic assessment, its utility as a biomarker may be limited by inter-tumoral heterogeneity. This article is protected by copyright. All rights reserved.