Interplay between soluble CD74 and macrophage-migration inhibitory factor drives tumor growth and influences patient survival in melanoma

Yasunari Fukuda,Sung-Nam Cho,Jeffrey E Lee,Suhendan Ekmekcioglu,Jared K Burks,Victor M Lopez,Dave S B Hoon,Suyeon Ryu,Jason Roszik,Elizabeth A Grimm,Matias A Bustos

doi:10.1038/s41419-022-04552-y

Abstract

Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of sCD74 was observed primarily in melanoma cell lines as well as a THP-1 line of macrophages from monocytes and primary macrophages, especially in response to interferon-γ (IFN-γ). A predominant form that showed clinical relevance was the 25-KDa sCD74, which originated from the 33-KDa isoform of CD74. The release of this sCD74 was regulated by either a disintegrin and metalloproteinase-mediated cell-surface cleavage or cysteine-protease-mediated lysosomal cleavage, depending on cell types. Both recombinant and THP-1 macrophage-released endogenous sCD74 suppressed melanoma cell growth and induced apoptosis under IFN-γ stimulatory conditions via inhibiting the MIF/CD74/AKT-survival pathway. Our findings demonstrate that the interplay between sCD74 and MIF regulates tumor progression and determines patient outcomes in advanced melanoma.

Highlights

Inflammation is a hallmark of various types of cancers, including melanoma [1]
High serum Soluble CD74 (sCD74) to migration inhibitory factor (MIF) ratio was associated with favorable patient survival Serum concentrations of sCD74 and MIF in two independent cohorts of melanoma patients [5, 6] and in NHDs were measured
We validated that serum sCD74 and MIF levels were elevated in patients with stage-IIIB/C melanoma in cohort 2 compared with NHDs (Fig. 1B, D). sCD74 and MIF levels were positively correlated in both melanoma patients and NHDs (Fig. 1E, F)

Summary

INTRODUCTION

Inflammation is a hallmark of various types of cancers, including melanoma [1]. Inflammation is involved in multistage carcinogenesis, tumorigenesis, and tumor resistance. A plethora of intrinsic molecules and structural components released by either tumor cells or surrounding cells evokes a wide range of inflammatory responses. These inflammatory stimuli successively alter the phenotypic and functional characteristics of cancer cells to be more vulnerable toward tumor progression [2, 3]. Previous work by our group showed that autocrine MIF–CD74 interactions in response to interferon-γ (IFN-γ) enhanced the phospho-AKT (pAKT), which sequentially induced the expression of inflammatory cytokines and tumor progression in melanoma [5]. We sought to determine the clinical implications of sCD74 and their biological functions upon interaction with MIF in melanoma

RESULTS

MATERIALS AND METHODS

DISCUSSION