Single-cell transcriptomics reveals the heterogeneity of the immune landscape of IDH-wildtype high-grade gliomas.

Isocitrate dehydrogenase (IDH)-wildtype (WT) high-grade gliomas, especially glioblastomas, are highly aggressive and have an immunosuppressive tumor microenvironment. Although tumor-infiltrating immune cells are known to play a critical role in glioma genesis, their heterogeneity and intercellular interactions remain poorly understood. In this study, we constructed a single-cell transcriptome landscape of immune cells from tumor tissue and matching peripheral blood mononuclear cells (PBMCs) from IDH-WT high-grade glioma patients. Our analysis identified two subsets of tumor-associated macrophages (TAMs) in tumors with the highest pro-tumorigenesis signatures, highlighting their potential role in glioma progression. We also investigated the T-cell trajectory and identified the aryl hydrocarbon receptor (AHR) as a regulator of T-cell dysfunction, providing a potential target for glioma immunotherapy. We further demonstrated that knockout of AHR decreased CAR T-cell exhaustion and improved CAR T-cell anti-tumor efficacy both in vitro and in vivo. Finally, we explored intercellular communication mediated by ligand-receptor interactions within the tumor microenvironment and PBMCs and revealed the unique cellular interactions present in the tumor microenvironment. Taken together, our study provides a comprehensive immune landscape of IDH-WT high-grade gliomas and offers potential drug targets for glioma immunotherapy.