Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma

Abstract

Purpose Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients’ tumor tissues. Experimental Design Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or relapse-free survival (RFS) in the retrospective discovery tissue microarray (TMA) (n = 158) were subsequently evaluated in an independent validation TMA (n = 114). Cox proportional hazards regression models were used to assess the association between survival parameters and covariates, the Kaplan-Meier method to estimate the distribution of survival, and the log-rank test to compare distributions. Results Expression of CD74 on melanoma cells was unique, and in the discovery TMA it associated with favorable patient outcome (OS: HR, 0.53, P = 0.01 and RFS: HR, 0.56; P = 0.01). The validation dataset confirmed the CD74 prognostic significance and revealed that the absence of MIF and iNOS was also associated with poor survival parameters. Consistent with the protein observation, tumor CD74 mRNA expression also correlated positively (p = 0.003) with OS in the melanoma TCGA dataset. Conclusions Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable RFS and OS in stage III melanoma. Low or negative expression of MIF in both TMAs, and of iNOS in the validation set also provided useful prognostic data. A disease-specific investigation of CD74’s functional significance is warranted, and other markers appear intriguing to pursue.

Spatially Resolved Transcriptomics Enables Dissection of Genetic Heterogeneity in Stage III Cutaneous Malignant Melanoma

“…The gene expression profile of the lymphoid factor involved HLA genes and CD74, the latter of which has been shown to be associated with favorable recurrence-free survival and overall survival in stage III melanoma (42). The expression of HLA genes is essential for immune-mediated regression of metastases, with certain HLA variants causing resistance to immune therapy (43)(44).…”

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

“…Expression levels can then be correlated with patient survival and therapeutic response (Ekmekcioglu et al, 2016). …”

Macrophage migration inhibitory factor‐CD74 interaction regulates the expression of programmed cell death ligand 1 in melanoma cells

“…It has usually been identified as a chaperone of MHC class II Dα and Dβ chains, but a small proportion of CD74 is found on the cell surface independent of the MHC class II complex, where it functions as a receptor for MIF . CD74 has been reported to be expressed in various malignancies and serves as a prognostic factor, disease progression marker, and promoter of invasion and metastasis . Interaction between MIF and CD74 has been reported to regulate the expression of various genes, including IL‐6 , IL‐8 , and BCL‐2 .…”

“…γ-Interferon (IFN-γ) stimulation upregulates expression levels of programmed cell death ligand 1 (PD-L1) mediated by the activation of macrophage migration inhibitory factor (MIF)-CD74 interactions, which is induced by the upregulation of cell surface CD74 expression by IFN-γ stimulation has been reported to be expressed in various malignancies and serves as a prognostic factor, disease progression marker, and promoter of invasion and metastasis. 17,[34][35][36][37][38] Interaction between MIF and CD74 has been reported to regulate the expression of various genes, including IL-6, IL-8, and BCL-2. 17,39,40 Expression of BCL-2 contributes to apoptosis and chemotherapy resistance.…”