OS05.4.A Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation. (5th September 2022)

• Record Type: Journal Article
• Authors: Schmassmann, P; Roux, J; Dettling, S; Hogan, S; Herter, S; Bacac, M; Shekarian, T; Martins, T A; Ritz, M; Hutter, G
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 2
• Page Start: ii13
• Page End: ii13
• Publication Date: 2022-09-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac174.040
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Clinical trials of systemic T cell checkpoint blockade in GBM patients showed only disappointing results. This may be attributed in part to the immunosuppressive components of the GBM immune tumor microenvironment (iTME). Therefore, major efforts have been undertaken to describe the GBM iTME on a single cell level. However, human data on the composition of the iTME in different tumor regions (contrast enhancing tumor center versus peripheral infiltration zone) remain scarce. Material and Methods: Here, we performed high-depth single-cell RNA sequencing (scRNA-seq) on patient-matched biopsies from tumor center and the peripheral infiltration zone of five primary GBM patients. Additionally, peripheral blood mononuclear cells (PBMC) of the same patients were included in the analysis to explore the transcriptional changes occurring during tumor infiltration of circulating immune cells. Main findings of the transcriptional analysis were confirmed by flow cytometry. Results: Through analysis of > 45'000 cells, we revealed a distinct regional transcriptional profile of microglia (MG) and monocyte-derived macrophages (MdM), a non-reactive/exhausted MG subcluster in the GBM iTME and an impaired interferon-response signature in the tumor-peripheral cytotoxic cell compartment. Comparing CD8 + T cells from the tumor periphery to PBMC-derived CD8 + T cells of the same patient revealed CX3CR1 high and CX3CR1 int CD8 + T cells with effector and memory phenotype, respectively, enriched in the PBMC but lacking in the tumor periphery. Tumor peripheral CD8 + T cells shared features with tissue-resident memory CD8 + T cells with exhausted effector functions. Conclusion: Our analysis provides a large-scale dissection of GBM-associated cell types complemented by patient-matched PBMCs, serving as a high dimensional reference map of the human GBM iTME.