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

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 CD 74 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 ‐ CD 74 interaction. Immunohistochemical analyses of 97 melanoma tissue samples showed significant correlations between CD 74 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 CD 74 following IFN ‐γ stimulation, showed upregulation of PD ‐L1 levels by IFN ‐γ stimulation. This was suppressed by further treatment with the MIF ‐ CD 74 interaction inhibitor, 4‐iodo‐6‐phenylpyrimidine. In the analysis of melanoma cell line WM 1361A, which constitutively expresses PD ‐L1, CD 74, and MIF in its non‐treated state, treatment with 4‐iodo‐6‐phenylpyrimidine and transfection of si RNA s targeting MIF and CD 74 significantly suppressed the expression of PD ‐L1. Together, the results indicated that MIF ‐ CD 74 interaction directly regulated the expression of PD ‐L1 and helps tumor cells escape from antitumorigenic immune responses. In conclusion, the MIF ‐ CD 74 interaction could be a therapeutic target in the treatment of melanoma patients.