Original ArticlesIDO1 Expression in Melanoma Metastases Is Low and Associated With Improved Overall SurvivalLynch, Kevin T. MD*; Gradecki, Sarah E. MD†; Kwak, Minyoung MD*; Meneveau, Max O. MD*; Wages, Nolan A. PhD‡; Gru, Alejandro A. MD†; Slingluff, Craig L. Jr MD*Author Information Departments of *Surgery †Pathology ‡Public Health Sciences, University of Virginia, Charlottesville, VA Conflicts of Interest and Source of Funding: Support provided by the United States Public Health Services Training Grants T32HL007849 (K.T.L.), T32CA009109-41 (M.K.), and T32CA163177 (M.K., M.O.M.), as well as the Farrow Fellowship and Rebecca Clary Harris Memorial Fellowship, both from the University of Virginia (M.K.). Additional support was received from the Biostatistics Shared Resource, University of Virginia Cancer Center (N.A.W.) and the Cancer Center Support Grant P30CA044579 (C.L.S.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Craig L. Slingluff Jr, MD, Department of Surgery, Division of Surgical Oncology, University of Virginia, 1215 Lee Street, Charlottesville, VA 22908 (e-mail: [email protected]). The American Journal of Surgical Pathology: June 2021 - Volume 45 - Issue 6 - p 787-795 doi: 10.1097/PAS.0000000000001622 Buy SDC Metrics Abstract Indoleamine 2-3 dioxygenase 1 (IDO1) expression may contribute to immunologic escape by melanoma metastases. However, a recent clinical trial failed to identify any clinical benefits of IDO1 inhibition in patients with unresectable metastatic melanoma, and prior characterizations of IDO1 expression have predominately studied primary lesions and local metastases, generating uncertainty regarding IDO1 expression in distant metastases. We hypothesized that IDO1 expression in such lesions would be low and correlated with decreased overall survival (OS). Metastases from patients (n=96) with stage IIIb to IV melanoma underwent tissue microarray construction and immunohistochemical staining for IDO1. Th1-related gene expression was determined quantitatively. Associations between OS and IDO1 expression were assessed with multivariate models. Of 96 metastatic lesions, 28% were IDOpos, and 85% exhibited IDO1 expression in <10% of tumor cells. IDOpos lesions were associated with improved OS (28.9 vs. 10.5 mo, P=0.02) and expression of Th1-related genes. OS was not associated with IDO1 expression in a multivariate analysis of all patients; however, IDO1 expression (hazard ratio=0.25, P=0.01) and intratumoral CD8+ T-cell density (hazard ratio=0.99, P<0.01) were correlated with OS in patients who underwent metastasectomy with curative-intent. IDOpos metastases were less likely to recur after metastasectomy (54% vs. 16%, P=0.01). IDO1 expression was low in melanoma metastases and correlated with OS after metastasectomy with curative-intent. Intratumoral CD8+ T cells and Th1-related genes were correlated with IDO1 expression, as was tumor recurrence. These suggest that IDO1 expression may be a marker of immunologic tumor control, and may inform participant selection in future trials of IDO1 inhibitors. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.