Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation

• DOI: 10.7554/elife.92678.2
• Publication Date: 2023-12-21T19:35:56Z
• Authors: Philip Schmassmann; Julien Roux; Steffen Dettling; Sabrina Hogan; Tala Shekarian; Tomás A Martins; Marie-Françoise Ritz; Sylvia Herter; Marina Bacac; Gregor Hutter
• Keywords: 0303 health sciences; QH301-705.5; Brain Neoplasms; Science; Macrophages; Q; glioblastoma; R; scRNAseq; Glioma; CD8-Positive T-Lymphocytes; 03 medical and health sciences; Leukocytes; Tumor Microenvironment; tumor microenvironment; Medicine; Humans; Biology (General); Glioblastoma; Cancer Biology

Glioblastoma (GBM) harbors a highly immunosuppressive tumor microenvironment (TME) which influences glioma growth. Major efforts have been undertaken to describe the TME on a single-cell level. However, human data on regional differences within the TME remain scarce. Here, we performed high-depth single-cell RNA sequencing (scRNAseq) on paired biopsies from the tumor center, peripheral infiltration zone and blood of five primary GBM patients. Through analysis of >45,000 cells, we revealed a regionally distinct transcription profile of microglia (MG) and monocyte-derived macrophages (MdMs) and an impaired activation signature in the tumor-peripheral cytotoxic-cell compartment. Comparing tumor-infiltrating CD8+ T cells with circulating cells identified CX3CR1high and CX3CR1int CD8+ T cells with effector and memory phenotype, respectively, enriched in blood but absent in the TME. Tumor CD8+ T cells displayed a tissue-resident memory phenotype with dysfunctional features. Our analysis provides a regionally resolved mapping of transcriptional states in GBM-associated leukocytes, serving as an additional asset in the effort towards novel therapeutic strategies to combat this fatal disease.