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An Injury-like Signature of the Extracellular Glioma Metabolome. Cancers Aberrant metabolism is a hallmark of malignancies including gliomas. Intracranial microdialysis enables the longitudinal collection of extracellular metabolites within CNS tissues including gliomas and can be leveraged to evaluate changes in the CNS microenvironment over a period of days. However, delayed metabolic impacts of CNS injury from catheter placement could represent an important covariate for interpreting the pharmacodynamic impacts of candidate therapies. Intracranial microdialysis was performed in patient-derived glioma xenografts of glioma before and 72 h after systemic treatment with either temozolomide (TMZ) or a vehicle. Microdialysate from GBM164, an IDH-mutant glioma patient-derived xenograft, revealed a distinct metabolic signature relative to the brain that recapitulated the metabolic features observed in human glioma microdialysate. Unexpectedly, catheter insertion into the brains of non-tumor-bearing animals triggered metabolic changes that were significantly enriched for the extracellular metabolome of glioma itself. TMZ administration attenuated this resemblance. The human glioma microdialysate was significantly enriched for both the PDX versus brain signature in mice and the induced metabolome of catheter placement within the murine control brain. These data illustrate the feasibility of microdialysis to identify and monitor the extracellular metabolome of diseased versus relatively normal brains while highlighting the similarity between the extracellular metabolome of human gliomas and that of CNS injury. 10.3390/cancers16152705
Immune landscape of isocitrate dehydrogenase-stratified primary and recurrent human gliomas. Neuro-oncology BACKGROUND:Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear. METHODS:In this study, we used sequential single-cell transcriptomics on 144 678 and spectral cytometry on over 2 million immune cells encompassing 48 human gliomas to decipher their immune landscape. RESULTS:We identified 22 distinct immune cell types that contribute to glioma immunity. Specifically, brain-resident microglia (MG) were reduced with a concomitant increase in CD8+ T lymphocytes during glioma recurrence independent of IDH status. In contrast, IDH-wild type-associated patterns, such as an abundance of antigen-presenting cell-like MG and cytotoxic CD8+ T cells, were observed. Beyond elucidating the differences in IDH, relapse, and treatment-associated immunity, we discovered novel inflammatory MG subpopulations expressing granulysin, a cytotoxic peptide that is otherwise expressed in lymphocytes only. Furthermore, we provide a robust genomic framework for defining macrophage polarization beyond M1/M2 paradigm and reference signatures of glioma-specific tumor immune microenvironment (termed GlioTIME-36) for deconvoluting transcriptomic datasets. CONCLUSIONS:This study provides advanced optics of the human pan-glioma immune contexture as a valuable guide for translational and clinical applications. 10.1093/neuonc/noae139
Comprehensive analysis and experiments identified ANXA1 as an unfavorable prognosticator in glioma. Translational oncology BACKGROUND:ANXA1 was upregulated in gliomas in previous bulk sequencing studies. we examined the role of ANXA1 in glioma using bioinformatics analysis and experiments. METHODS:Two cohorts were adopted to validate the prognostic value of ANXA1 in gliomas. Real-time quantitative PCR and western blotting were performed on samples for further validation. Using the data of GSE162631, ANXA1 expression was analyzed in different cells in glioblastoma specimen. In different groups, lentiviral vector or the empty vector was used to construct cell lines. Wound-healing assay, along with Transwell assay, was conducted to assess the migration and invasion of glioma cells. Animal studies were conducted to examine the role of ANXA1 in gliomas. RESULTS:ANXA1 expression was associated with overall survival in glioma patients. In glioblastomas, ANXA1 expression was higher than in low-grade gliomas. Among patients receiving chemo- or radiotherapy, high ANXA1 expression presented a shorter overall survival. Single-cell sequencing showed that ANXA1 was expressed in a higher proportion and level in glioblastomas cells than in normal cells; whereas, ANXA1 was enriched in T cells among immune cells. As shown in experiments, knockdown of ANXA1 could attenuate the proliferation, migration and invasion of glioma cells in vitro and vivo, thereby improving the prognosis of animals. CONCLUSIONS:ANXA1 can promote the proliferation, migration and invasion of glioma; its expression is positively correlated with immune response and poor prognosis of glioma. The cancer-promoting mechanisms of ANXA1 in glioma and its correlation with the functional status of glioma patients warrant further investigation. 10.1016/j.tranon.2025.102286
Therapeutic approaches to modulate the immune microenvironment in gliomas. NPJ precision oncology Immunomodulatory therapies, including immune checkpoint inhibitors, have drastically changed outcomes for certain cancer types over the last decade. Gliomas are among the cancers that have seem limited benefit from these agents, with most trials yielding negative results. The unique composition of the glioma immune microenvironment is among the culprits for this lack of efficacy. In recent years, several efforts have been made to improve understanding of the glioma immune microenvironment, aiming to pave the way for novel therapeutic interventions. In this review, we discuss some of the main components of the glioma immune microenvironment, including macrophages, myeloid-derived suppressor cells, neutrophils and microglial cells, as well as lymphocytes. We then provide a comprehensive overview of novel immunomodulatory agents that are currently in clinical development, namely oncolytic viruses, vaccines, cell-based therapies such as CAR-T cells and CAR-NK cells as well as antibodies and peptides. 10.1038/s41698-024-00717-4