Cell Surface CD74–MIF Interactions Drive Melanoma Survival in Response to Interferon-γ

Abstract

While melanoma is believed to be a highly immunogenic tumor and recent developments in immunotherapies are promising. Interferon-γ (IFN-γ) produced by immune cells plays a crucial role in tumor immune surveillance; however, it has also been reported to be pro-tumorigenic. In the current study, we found that IFN-γ enhances the expression of CD74, which interacts with its ligand, macrophage migration inhibitory factor (MIF), and thereby activates the PI3K/AKT pathway in melanoma, promoting tumor survival. IFN-γ increased phosphorylation of AKT Ser473 and upregulated total and cell surface expression of CD74 in human melanoma cell lines tested. CD74 was highly expressed in melanoma tissues. Moreover, the expression of CD74 on tumor cells correlated with plasma IFN-γ levels in melanoma patient samples. In our analysis of melanoma cell lines, all produced MIF constitutively. Blockade of CD74-MIF interaction reduced AKT phosphorylation and expression of pro-tumorigenic molecules, including interleukin-6, interleukin-8 and BCL-2. Inhibition of CD74-MIF interaction significantly suppressed tumor growth in the presence of IFN-γ in our xenograft mouse model. Thus, we conclude that IFN-γ promotes melanoma cell survival by regulating CD74-MIF signaling, suggesting that targeting the CD74-MIF interaction under IFN-γ–stimulatory conditions would be an effective therapeutic approach for melanoma.

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

“…Although many markers have been noted extensively in the literature, in melanoma we have identified inflammatory cytokines IL-1α IL-1β and IL-6 (29) but none of these proved prognostic in our controlled and parallel studies shown here. In a previous functional study we observed that an MIF-CD74 autocrine interaction upregulated by exogenous IFN-γ, promoted the phosphorylation of AKT Ser473 and drove expression of such inflammatory cytokines (30), presenting a potentially protumor circuitous or alternative function when MIF is present, which may be likely in a subset of tumors after exposure to IFN-γ. These findings could be specifically important as we observed this effect regardless of the BRAF and NRAS mutation status.…”

Up-Regulation of CD74 Expression in Parietal Epithelial Cells in a Mouse Model of Focal Segmental Glomerulosclerosis

“…By immunohistochemistry, CD74 staining was observed to be co-localized with CD44 in some epithelial cells lining the BC in ADR-injured glomeruli, suggesting a role for CD74 expression in PEC activation. Although recent studies have suggested possible roles for the CD74-CD44 receptor complex and its ligand MIF in tumor cell proliferation [13,14,15,16], their roles in kidney diseases have not been elucidated; therefore, we attempted to evaluate CD74 expression in PEC activation and performed comparative analysis of CD74 and other PEC markers.…”

“…CD74 acts as a cell membrane receptor for the macrophage migration inhibitory factor (MIF), and the formation of the CD44-CD74 complex initiates the signaling pathway triggered by MIF in macrophages [9] and B cells [10,11,12], inducing cell proliferation and survival. Moreover, several studies suggested a role for CD74 expression in the progression of thyroid, breast, pancreatic, skin and gastrointestinal tract cancers [13,14,15,16]; however, only a few studies were conducted to evaluate the role of CD74 expression and that of CD74-CD44 complex in kidney diseases [17,18]. …”

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

“…On the basis of previous findings that IFN‐γ upregulates both PD‐L1 and cell surface CD74 expression, we hypothesized that the MIF‐CD74 interaction mediated the expression of PD‐L1 after stimulation by IFN‐γ. To test this hypothesis, we treated 2 melanoma cell lines, A375 and SB2, with IFN‐γ and an antagonist of the MIF‐CD4 interaction, 4‐IPP.…”

“…In a previous analysis of melanoma patient samples, serum IFN‐γ levels and CD74 expression levels in tumor cells showed a significant correlation. In addition, treating melanoma cell lines with recombinant IFN‐γ protein resulted in upregulation of cell surface CD74 protein levels …”