MIF-Induced CD74+ Microglia and Macrophages Promote Progression of Brain Metastasis and Are Clinically Relevant across Central Nervous System Disorders
Menée notamment à l'aide de modèles murins, d'échantillons de métastases cérébrales d'origine humaine et de données de séquençage d'ARN, cette étude met en évidence un mécanisme par lequel le facteur MIF, sécrété par les cellules cancéreuses, favorise la progression des métastases cérébrales en déclenchant, lors de sa liaison au récepteur CD74 des cellules microgliales et des macrophages, la translocation de ce dernier vers le noyau cellulaire puis l'activation d'un programme transcriptionnel qui modifie les cellules myéloïdes
The upregulation of CD74, a chaperone involved in MHC-II antigen processing, has been mostly interpreted as indicative of antigen presentation in multiple brain disorders. However, CD74 expression has also been described in cancer cells across multiple tumor types and in the tumor microenvironment, notably in glioma. In this study, we found that the presence of CD74+ microglia/macrophages, which was induced by increased levels of interferon
γ in brains affected by metastases, did not relate to its canonical pathway. Instead, the alternative function of CD74 as a cytokine receptor was pivotal. Proliferating cancer cells produced high levels of the ligand migration inhibitory factor (MIF) that bound the CD74 receptor and induced its translocation to the nucleus where it activated an NF-κB
–dependent program that promoted metastatic progression. In patients, a CD74 signature was associated with more aggressive progression of brain metastatic disease, although it had no clinical correlation with the matched primary tumor. Interestingly, a pan-disease noncanonical and clinically relevant signature derived from the CD74+ myeloid population was identified that occurred in additional brain disorders, including Alzheimer's disease and multiple sclerosis. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreased brain metastasis in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor–agnostic manner. These findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a vulnerability that could be exploited therapeutically against brain metastases and possibly other brain disorders.
Cancer Research , article en libre accès, 2026