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Cancer Sci. 2019 Jul;110(7):2273-2283. doi: 10.1111/cas.14038. Epub 2019 May 29.

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

Author information

1
Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
2
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Abstract

Expression of programmed cell death ligand 1 (PD-L1) on tumor cells contributes to cancer immune evasion by interacting with programmed cell death 1 on immune cells. γ-Interferon (IFN-γ) has been reported as a key extrinsic stimulator of PD-L1 expression, yet its mechanism of expression is poorly understood. This study analyzed the role of CD74 and its ligand macrophage migration inhibitory factor (MIF) on PD-L1 expression, by immunohistochemical analysis of melanoma tissue samples and in vitro analyses of melanoma cell lines treated with IFN-γ and inhibitors of the MIF-CD74 interaction. Immunohistochemical analyses of 97 melanoma tissue samples showed significant correlations between CD74 and the expression status of PD-L1 (P < .01). In vitro analysis of 2 melanoma cell lines, which are known to secrete MIF constitutively and express cell surface CD74 following IFN-γ stimulation, showed upregulation of PD-L1 levels by IFN-γ stimulation. This was suppressed by further treatment with the MIF-CD74 interaction inhibitor, 4-iodo-6-phenylpyrimidine. In the analysis of melanoma cell line WM1361A, which constitutively expresses PD-L1, CD74, and MIF in its non-treated state, treatment with 4-iodo-6-phenylpyrimidine and transfection of siRNAs targeting MIF and CD74 significantly suppressed the expression of PD-L1. Together, the results indicated that MIF-CD74 interaction directly regulated the expression of PD-L1 and helps tumor cells escape from antitumorigenic immune responses. In conclusion, the MIF-CD74 interaction could be a therapeutic target in the treatment of melanoma patients.

KEYWORDS:

CD74; PD-L1; interferon gamma; macrophage migration inhibitory factor; melanoma

PMID:
31069878
PMCID:
PMC6609804
DOI:
10.1111/cas.14038
[Indexed for MEDLINE]
Free PMC Article

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