Abstract
Single-cell technologies allow precise identification of tumor composition at the single-cell level, providing high-resolution insights into the intratumoral heterogeneity and transcriptional activity of cells in the tumor microenvironment (TME) that previous approaches failed to capture. Malignant gliomas, the most common primary brain tumors in adults, are genetically heterogeneous and their TME consists of various stromal and immune cells playing an important role in tumor progression and responses to therapies. Previous gene expression or immunocytochemical studies of immune cells infiltrating TME of malignant gliomas failed to dissect their functional phenotypes. Single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF) are powerful techniques allowing quantification of whole transcriptomes or >30 protein targets in individual cells. Both methods provide unprecedented resolution of TME. We summarize the findings from these studies and the current state of knowledge of a functional diversity of immune infiltrates in malignant gliomas with different genetic alterations. A precise definition of functional phenotypes of myeloid and lymphoid cells might be essential for designing effective immunotherapies. Single-cell omics studies have identified crucial cell subpopulations and signaling pathways that promote tumor progression, influence patient survival or make tumors vulnerable to immunotherapy. We anticipate that the widespread usage of single-cell omics would allow rational design of oncoimmunotherapeutics.
Highlights
Single-cell omics studies verified many previous assumptions and provided strong evidence for the anticipated diversity of myeloid and lymphoid infiltrates in the glioma tumor microenvironment (TME)
A ratio of tumor infiltrating microglia and monocytes-derived macrophages is different in IDH-wt and IDH-mut gliomas, with the predominance of microglia and lower infiltration of lymphocytes in the later
This suggests that cytokines/chemokines released by immunomodulatory macrophages may drive T-cell enrichment in TME of IDH-wt gliomas
Summary
Gliomas are tumors of the central nervous system (CNS) that originate from neural stem cells, or astrocytic or oligodendrocytic progenitor cells. Aberrant expression or mutations in genes such as EGFR, NF1, and PDGFRA/IDH1 allowed the delineation of the classical, mesenchymal, and proneural GBM subtypes, respectively. The IDH-mutant non-codel lower grade gliomas (LGG) and GBM were dissected based on the genome-wide patterns of DNA methylation, into two separate subgroups (G-CIMP-low and G-CIMP-high). This dissection is important as the G-CIMP-low subset had an unfavorable clinical outcome [9]. Copy number amplifications of the CDK4, EGFR, and PDGFRA loci and mutations in the NF1 locus define GBM states: neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocytelike (AC-like), and mesenchymal-like (MES-like) states While their relative frequency varies between tumors, genetic alterations in CDK4, PDGFRA, EGFR, and NF1 define a predominant state [12,13]. Collective data suggest that the molecularly distinct GBM subtypes representing various functional states have a profound impact on their microenvironment and this notion is supported by the data from mouse GBM models showing that well-defined driver mutations may create unique microenvironments [14]
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