Single-cell RNA sequencing reveals immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma

Recent studies have shown the importance of the dynamic tumor microenvironment (TME) in high-grade gliomas (HGGs). In particular, myeloid cells are known to mediate immunosuppression in glioma; however, it is still unclear if myeloid cells play a role in low-grade glioma (LGG) malignant progression. Here, we investigate the cellular heterogeneity of the TME using single-cell RNA sequencing in a murine glioma model that recapitulates the malignant progression of LGG to HGG. LGGs show increased infiltrating CD4+ and CD8+ T cells and natural killer (NK) cells in the TME, whereas HGGs abrogate this infiltration. Our study identifies distinct macrophage clusters in the TME that show an immune-activated phenotype in LGG but then evolve to an immunosuppressive state in HGG. We identify CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Targeting these intra-tumoral macrophages in the LGG stage may attenuate their immunosuppressive properties and impair malignant progression. [Display omitted] •Macrophages exhibit signatures of immune activation during LGG•Macrophages evolve to an immunosuppressive state in HGG•T cell infiltration is restricted in HGG•CD74-MIF axis is upregulated in tumor-infiltrating macrophages in LGG and HGG Rajendran et al. identified distinct macrophages that show immune activation signatures in the LGG stage and immunosuppressive features in the HGG stage. The CD74-MIF axis is upregulated in the macrophages in the LGG stage and may serve as a potential target for tumor-infiltrating macrophages prior to malignant progression.