Biology subjects

Schmassmann, P.

Publications and source records attributed to Schmassmann, P..

4 recordsLinked to original sources

bioRxiv2023

Multidimensional analysis of matched primary and recurrent glioblastoma identifies Fcgamma receptors upregulation on microglia as a contributor of tumor recurrence.

O_LIBackground: Glioblastoma (GBM) is a lethal brain tumor without effective treatment options. The aim of this study was to characterize longitudinal tumor immune microenvironment (iTME) changes in order to find potential actionable targets to prevent GBM-induced immune evasion mechanisms. C_LIO_LIMethods: This study included 15 patient-matched treatment-naive WHO grade 4 primary (pGBM) and recurrent (rGBM) tumors. RNA and proteins extracted from fresh frozen tumor samples from matched pGBM and rGBM were profiled via transcriptomics and proteomics, respectively. A tissue microarray containing paired formalin-fixed paraffin-embedded tumor samples was processed for spatial transcriptomics analysis. C_LIO_LIResults: Differentially expressed genes and proteins between pGBM and rGBM were involved in pathways responsible for synapse development and myelination which have been shown to play a role in GBM recurrence. By categorizing patients into short and long time-to-relapse (STTR vs LTTR), we identified genes positively or negatively associated with TTR. Expression of Fc{gamma} receptors and complement system genes such as FCGR1A (CD64), FCGR3A and C3 in rGBM samples were negatively correlated with TTR, whereas expression of DNMT1/3A, and SMARCA4, involved in DNA methylation, were positively correlated with TTR. Spatial transcriptomic analysis of the tumor cell compartment showed enrichment of oligodendrocytes in rGBM, whereas the myeloid cell compartment switched from quiescent to activated microglia, was enriched in B and T cells, specifically in rGBM with STTR. C_LIO_LIConclusions: Our results uncover a role for CD64-expressing activated microglia in GBM recurrence and suggest that interfering with these cells may represent a therapeutic option for hindering GBM relapse. C_LI Key pointsO_LITranscriptomic and proteomic differences exist between patient-paired primary and recurrent GBM tumors C_LIO_LIHigh expression of Fcy receptors genes on activated microglia at tumor recurrence is associated with shorter time to relapse. C_LI Importance of this studyIn glioblastoma (GBM), the tumor recurs in almost all cases after standard treatment such as surgery and chemo-radiotherapy. In this study, we longitudinally evaluated the immune- and neoplastic compartments using transcriptomic, proteomic, and spatial transcriptomics in patient-matched treatment-naive and recurrent tumor samples. By correlating gene expression with time-to-relapse, we identified a geneset associated with treatment resistance and faster tumor recurrence. Moreover, this study highlighted the plasticity of the myeloid compartment during disease progression and an unfavorable role of activated microglia in tumor recurrence.

cancer biology↗

bioRxiv2022

The Siglec-sialic acid-axis is a target for innate immunotherapy of glioblastoma

Glioblastoma (GBM) is the most aggressive form of primary brain tumor, for which effective therapies are urgently needed. Cancer cells are capable of evading clearance by phagocytes such as microglia and monocyte-derived cells through engaging tolerogenic programs. Here, we found that high level of Siglec-9 expression correlates with reduced survival in GBM patients. Using conditional knockouts of Siglec-E, the murine functional homologue of Siglec-9, together with single-cell RNA sequencing, we demonstrated significant pro-phagocytosis effects in microglia and monocyte-derived cells in the absence of Siglec-E. Loss of Siglec-E on monocyte-derived cells enhances antigen cross-presentation and production of pro-inflammatory cytokines, resulting in more efficient T cell priming. This bridging of innate and adaptive responses delays tumor growth and results in prolonged survival. Further, we showed synergistic activity of Siglec-E blockade in combinatorial immunotherapies and demonstrate its translational potential against GBM.

cancer biology↗

bioRxiv2022

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

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 > 45000 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.

cancer biology↗

bioRxiv2022

Immunotherapy of glioblastoma explants induces interferon-γ responses and immune cell rearrangements in tumor center, but not periphery

Recent therapeutic strategies for glioblastoma (GBM) aim at targeting immune tumor microenvironment (iTME) components to induce antitumoral immunity. A patient-tailored, ex vivo drug testing and response analysis platform for GBM would facilitate personalized therapy planning, provide insights into treatment-induced immune mechanisms in the iTME, and enable the discovery of biomarkers of therapy response and resistance. We cultured 47 GBM explants from tumor center and periphery from 7 patients in perfusion bioreactors to assess iTME responses to immunotherapy. Explants were exposed to antibodies blocking the immune checkpoints CD47, PD-1 or or their combination, and were analyzed by highly multiplexed microscopy (CODEX, co-detection by indexing) using an immune-focused 55-marker panel. Culture media were examined for changes of soluble factors including cytokines, chemokines and metabolites. CODEX enabled the spatially resolved identification and quantification of >850,000 single cells in explants, which were classified into 10 cell types by clustering. Explants from center and periphery differed significantly in their cell type composition, their levels of soluble factors, and their responses to immunotherapy. In a subset of explants, culture media displayed increased interferon-{gamma} levels, which correlated with shifts in immune cell composition within specific tissue compartments, including the enrichment of CD4+ and CD8+ T cells within an adaptive immune compartment. Furthermore, significant differences in the expression levels of functional molecules in innate and adaptive immune cell types were found between explants responding or not to immunotherapy. In non-responder explants, T cells showed higher expression of PD-1, LAG-3, TIM-3 and VISTA, whereas in responders, macrophages and microglia showed higher cathepsin D levels. Our study demonstrates that ex vivo immunotherapy of GBM explants enables an active antitumoral immune response within the tumor center in a subset of patients, and provides a framework for multidimensional personalized assessment of tumor response to immunotherapy.

cancer biology↗