Dissecting the Immune Microenvironment of Malignant Gliomas with Single-Cell Omic Reveals New Treatment Opportunities

Glioblastoma (GBM) is a most frequent and incurable primary brain tumor in adults. Tumor cells create the highly heterogeneous tumor microenvironment (TME) consisting of neoplastic, stromal and immune cells. Lack of reliable markers prevented the identification of cell subtypes and functional phenotypes of immune cells present in the GBM TME. Single-cell technologies provide high-resolution insights into the cellular and functional heterogeneity of TME that previous approaches failed to capture. Single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF) allow quantification of whole transcriptomes or > 30 proteins in individual cells. Single-cell omics revisited earlier assumptions and reveal diversity of myeloid and lymphoid infiltrates in gliomas. Sc-omics results uncovered the diversity of immune cells in malignant gliomas and different prevalence of immune cell populations in tumors with distinct genetic alterations. Occurrence of microglia and monocytes-derived macrophages differs in IDH-wt and IDH-mut gliomas influencing the accumulation and activation of T cells. Cytokines/chemokines released by immunomodulatory macrophages instigate the enrichment of regulatory T cells in TME of IDH-wt gliomas resulting in suppression of cytotoxic T cells. Across molecular glioblastoma subtypes, the mesenchymal (MES)-like state shows the increased accumulation of myeloid cells and T cells and worst survival. These studies disclosed discrete cell states and signaling pathways that promote tumor progression, influence patient survival or make tumors vulnerable to immunotherapy, which allows the rational design of oncoimmunotherapeutics. We assess recent attempts at targeting specific immune cell populations or enzymes in those populations to achieve anti-glioma effects or restore anti-tumor responses.