Abstract B18: The expression of CD74-regulated inflammatory markers in stage IV melanoma: Risk of CNS metastasis and patient survival
Authors: Ogata Dai , Kim Sun-Hee , Roszik Jason , Bassett Roland L , Grimm Elizabeth A , Ekmekcioglu Suhendan 
Published: June 2022

Abstract
Innate inflammatory features have been found in melanoma tumors from patients at all stages, and ongoing molecular analysis by us and others has identified specific inflammatory proteins expressed by tumors cells in those patients with the worst prognosis. We have previously observed impaired outcomes in patients with constitutive expression of inducible nitric oxide synthase (iNOS), Macrophage Migration Inhibitory Factor (MIF), and improved outcomes with CD74 expression in stage III melanoma (1-2). In this study, we tested our hypothesis that CD74-regulated inflammatory markers’ expression in stage IV melanoma tumors is associated with survival outcome and risk of developing CNS metastasis. We retrospectively identified 315 patients with stage IV melanoma. In a tissue microarray (TMA) of systemic metastasis specimens from these patients, we used immunohistochemical analysis to measure the expression of cells with CD74, MIF, iNOS, Nitrotyrosine (NT), cyclooxygenase (COX)-2, and microsomal prostaglandin E synthase-1 (mPGES1). We analyzed the association of those inflammatory markers with overall survival time (OS) and time to first CNS metastasis using Kaplan–Meier survival analyses. Tissue sections from 315 patients with distant metastatic melanoma were included in the TMA, of which 169 (54%) did not have CNS metastasis at the time of the last follow-up. The median age of the patients at the time of the stage IV diagnosis was 56 (range: 13–85 years). For OS, the expression of CD74 impacts overall survival in stage IV melanoma patients (p=0.0196). Moreover, the combination of tumor expression of CD74 and lack of MIF expression showed the advantage of OS in stage IV melanoma patients (p=0.0264). The expression of CD74 tended to be predictive of development or time to CNS metastasis. However, the expression of NT significantly impacted development or time to CNS metastasis (p=0.0008). To corroborate these findings, we further investigated the survival associations in the melanoma stage IV TCGA dataset for our markers of interest. Only high CD74 expression predicted better prognosis in stage IV melanoma patients when compared with low expression (p=0.0265). Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable OS in stage IV melanoma. The tumor NT expression strongly predicts an increased risk of developing CNS metastasis in those patients. Our understanding of complex cancer cell and their response in the chronic inflammation environment would help us develop better treatments for melanoma.
References
1. Grimm EA et al., Clin Cancer Res 2013;19:5557–63.
2. Ekmekcioglu S et al., Clin Cancer Res 2016;22(12):3016-24.
Citation Format: Dai Ogata, Sun-Hee Kim, Jason Roszik, Roland L Bassett Jr, Elizabeth A Grimm, Suhendan Ekmekcioglu. The expression of CD74-regulated inflammatory markers in stage IV melanoma: Risk of CNS metastasis and patient survival [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B18.