233 Evolutionary Analysis Identifies Early Responsive Macrophage Representing as Anti-tumor Myeloid Cell in Glioblastoma

Abstract

INTRODUCTION: Glioblastoma (GBM) has no effective treatments. Although immunotherapy has shown promise in certain cancer types, it has not been effective against GBM, largely due to its highly immunosuppressive tumor microenvironment (TMEs), which is rich in tumor-associated macrophages/microglia (TAMs). TAMs in late-stage GBM contribute to T-cell exhaustion and worsen prognosis, but the role of TAMs in earlier stages of tumor development is unclear. METHODS: By employing genetically engineered mouse models and human samples, we used spatiotemporal single-cell transcriptomics to investigate TAM evolution during GBM progression. RESULTS: We identified a previously unknown macrophage state, termed early responsive macrophage (ERM), that exhibited antitumoral activity. ERMs were found to be abundant in the early stages of GBM progression and spatially enriched in the invading edges of GBMs. ERMs are characterized by upregulated immune response signatures, particularly pathways related to antigen processing and presentation, as well as genes associated with phagocytosis and chemotaxis. Mechanistically, we identified QKI, a transcriptional co-activator, as a key player that activates antigen processing and presentation and MHCII expression in ERMs. Loss of QKI in TAMs is associated with the transformation of ERMs into exhausted tumor-infiltrating macrophages (TIMs), which promote an immune-suppressive TME. Therapeutically, enhancement of QKI's transcriptional co-factor activity greatly improved the efficacy of immune checkpoint blockade. CONCLUSIONS: Our study sheds light on the evolutionary trajectory of TAMs in GBM and presents a novel therapeutic approach to enhance their antitumoral activity, thereby constraining tumor growth.