Abstract 5083: Indoleamine 2-3 dioxygenase expression by metastatic melanoma cells correlates with increased overall survival
Authors: Lynch Kevin , Gradeki Sarah , Kwak Min , Gru Alejandro , Wages Nolan , Slingluff Craig 
Published: September 2020

Abstract
Though immunotherapy revolutionized the treatment of advanced melanoma, many patients fail to respond to checkpoint blockade, creating a pressing need to optimize the immune response to metastatic melanoma. Indoleamine 2-3 dioxygenase (IDO), which can be induced in a variety of cancer types and inhibits the immune response, has emerged as a potential target for future immunotherapies. Conflicting evidence exists regarding the prognostic significance of IDO expression in metastatic melanoma cells. We hypothesized that IDO expression by melanoma cells would correlate with decreased overall survival (OS). Skin or lymph node metastases from 89 patients with Stage III or IV melanoma were included in this study. Tissue microarrays (TMA) were constructed and immunohistochemical staining for IDO1 (Sigma Prestige, HPA 023072, 1:2,000 dilution) was performed. IDO staining in tumor cells was scored by an experienced dermatopathologist and was classified as positive (IDO+) when clear cytoplasmic staining was present in ≥1% of tumor cells. The main endpoint for analysis was OS as defined by the time from initial surgery to death. Multivariate Cox proportional hazards modeling was performed and Cox proportional hazards assumptions were tested using Schoenfield residual analysis. Following IHC staining, 32/89 patients were classified as IDO+ (36%). Comparison of patient demographics revealed that IDO+ patients were more likely to undergo resection with palliative intent and to have Stage IV disease. Tumor immunotype also varied by IDO status, with IDO+ patients more likely to have immunotype B or C lesions. Additionally, IDO+ tumors showed higher intratumoral density of CD20+ B cells, CD4+ and CD8+ T-cells, and FoxP3+ T-cells. Patients with IDO+ lesions had significantly better OS (median 31.6 vs 98.5 months, p-value&lt;0.01). In a multivariate model incorporating IDO expression, age, sex, disease stage, BRAF mutation status, PD-L1 expression, CD8+ T-cell infiltration density, and palliative surgical intent, only IDO expression and palliative surgical intent retained statistically significant associations with overall survival (HR=0.44, p-value=0.01). Contrary to our initial hypothesis, in this cohort of immunotherapy-naïve, stage III-IV melanoma patients, IDO expression by metastatic melanoma cells was correlated with improved OS, which persisted even after controlling for sex, age, disease stage, BRAF mutation and CD8+ T cell infiltrate. It seems likely that IDO expression by melanoma cells may be triggered by a pro-inflammatory cytokine milieu within the tumor microenvironment, as has been postulated by others. Whether the positive prognostic effect of IDO expression in Stage III and IV melanoma metastases we observed is attributable entirely to increased immune infiltrate within the tumor is unclear. Nonetheless, our findings, particularly in context of the failure an IDO1 inhibitor, Epacadostat, in a recent stage 3 clinical trial highlight the need for further investigation into the function of IDO1 in melanoma metastases.
Citation Format: Kevin Lynch, Sarah Gradeki, Min Kwak, Alejandro Gru, Nolan Wages, Craig Slingluff. Indoleamine 2-3 dioxygenase expression by metastatic melanoma cells correlates with increased overall survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5083.