Systemic and local immunosuppression in glioblastoma and its prognostic significance

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 28, 2024

The effectiveness of tumor therapy, especially immunotherapy and oncolytic virotherapy, critically depends on the activity host immune cells. However, various local systemic mechanisms immunosuppression operate in cancer patients. Tumor-associated involves deregulation many components immunity, including a decrease number T lymphocytes (lymphopenia), an increase levels or ratios circulating tumor-infiltrating immunosuppressive subsets [e.g., macrophages, microglia, myeloid-derived suppressor cells (MDSCs), regulatory (Tregs)], as well defective functions antigen-presenting, helper effector cell due to altered expression soluble membrane proteins (receptors, costimulatory molecules, cytokines). In this review, we specifically focus data from patients with glioblastoma/glioma before standard chemoradiotherapy. We discuss glioblastoma-related at baseline prognostic significance different (lymphocytes, CD4+ CD8+ cells, Tregs, natural killer (NK) neutrophils, MDSCs, dendritic cells), neutrophil-to-lymphocyte ratio (NLR), landscape isocitrate dehydrogenase ( IDH )-mutant gliomas, proneural, classical mesenchymal molecular subtypes, highlight features surveillance brain. All attempts identify reliable marker glioblastoma tissue have led contradictory results, which can be explained, among other things, by unprecedented level spatial heterogeneity infiltrate significant phenotypic diversity (dys)functional states subpopulations. High NLR is one most repeatedly confirmed independent factors for shorter overall survival carcinoma, its combination markers response inflammation significantly improves accuracy prediction; however, more prospective studies are needed confirm prognostic/predictive power NLR. call inclusion dynamic assessment blood inflammatory (e.g., absolute/total lymphocyte count, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte immune-inflammation index, index) all neuro-oncology rigorous evaluation comparison their individual combinatorial relative superiority.

Language: Английский

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The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 669 - 669

Published: Jan. 14, 2025

Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives growth and therapeutic resistance. Key pathways, including glycolysis, lactate production, lipid metabolism, are upregulated to sustain survival in the hypoxic nutrient-deprived microenvironment (TME), while glutamine tryptophan metabolism further contribute phenotype of GBM. These alterations impair immune cell function, leading exhaustion stress CD8+ CD4+ T cells favoring immunosuppressive populations such as regulatory (Tregs) M2-like macrophages. Recent studies emphasize role slow-cycling GBM (SCCs), lipid-laden macrophages, tumor-associated astrocytes (TAAs) reshaping GBM’s landscape reinforcing evasion. Genetic mutations, Isocitrate Dehydrogenase (IDH) Epidermal Growth Factor Receptor (EGFR) amplification, Phosphotase Tensin Homolog (PTEN) loss, drive offer potential targets for therapy. Understanding relationship between suppression critical overcoming This review focuses on rewiring GBM, its impact microenvironment, combining targeting with immunotherapy improve clinical outcomes patients.

Language: Английский

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The need for paradigm shift: prognostic significance and implications of standard therapy-related systemic immunosuppression in glioblastoma for immunotherapy and oncolytic virotherapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 8, 2024

Despite significant advances in our knowledge regarding the genetics and molecular biology of gliomas over past two decades hundreds clinical trials, no effective therapeutic approach has been identified for adult patients with newly diagnosed glioblastoma, overall survival remains dismal. Great hopes are now placed on combination immunotherapy. In immunotherapeutics generally tested after standard therapy (radiation, temozolomide, steroid dexamethasone) or concurrently temozolomide and/or steroids. Only a minor subset progressive/recurrent glioblastoma have benefited from immunotherapies. this review, we comprehensively discuss therapy-related systemic immunosuppression lymphopenia, their prognostic significance, implications immunotherapy/oncolytic virotherapy. The effectiveness immunotherapy oncolytic virotherapy (viro-immunotherapy) critically depends activity host immune cells. absolute counts, ratios, functional states different circulating tumor-infiltrating cell subsets determine net fitness cancer may various effects tumor progression, response, outcomes. Although immunosuppressive mechanisms operate glioblastoma/gliomas at presentation, immunological competence be significantly compromised by therapy, exacerbating tumor-related immunosuppression. Standard affects diverse subsets, including dendritic, CD4+, CD8+, natural killer (NK), NKT, macrophage, neutrophil, myeloid-derived suppressor (MDSC). Systemic lymphopenia limit system’s ability to target glioblastoma. Changes required increase success Steroid use, high neutrophil-to-lymphocyte ratio (NLR), low post-treatment total lymphocyte count (TLC) factors shorter retrospective studies; however, these clinically relevant variables rarely reported correlated response studies (e.g., checkpoint inhibitors, vaccines, viruses). Our analysis should help development more rational trial design decision-making treatment potentially improve efficacy

Language: Английский

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Extracellular Matrix Structure and Interaction with Immune Cells in Adult Astrocytic Tumors

Cellular and Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 44(1)

Published: July 5, 2024

Abstract The extracellular matrix (ECM) is a dynamic set of molecules produced by the cellular component normal and pathological tissues embryo adult. ECM acts as critical regulator in various biological processes such differentiation, cell proliferation, angiogenesis, immune control. most frequent primary brain tumors are gliomas far majority adult astrocytic (AATs). prognosis for patients with these neoplasms poor treatments modestly improves survival. In literature, there fair number studies concerning composition AATs, while relating regulation smaller. Circulating proteins have emerged promising biomarker that reflect general landscape tumor microenvironment may represent useful tool assessing disease activity. Given importance it can therapeutic prognostic purposes, aim our study to summarize properties components their effects on provide an overview interactions between major cells AATs. As field immunotherapy glioma quickly expanding, we retain current data together future organization functions will important insights into tuning immunotherapeutic approaches. Graphical

Language: Английский

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Radioimmunotherapy in glioblastoma multiforme: A hypothesis to benefit immune effects of radiotherapy with full potential

Medical Hypotheses, Journal Year: 2025, Volume and Issue: 196, P. 111582 - 111582

Published: Jan. 31, 2025

Language: Английский

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A Characterization of the Immune Cells in Immunocompetent and Immunodeficient Mice with Orthotopic Brain Tumors.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: May 4, 2025

Abstract Background Glioblastoma, while considered rare, is characterized by poor survival and few treatment advances for over 20 years. New options brain cancers are, therefore, desperately needed. Active research that being conducted in immunotherapy glioblastoma other primary may be hampered the lack of detailed studies characterize different immune compartments orthotopic murine tumor models. Methods We used glioma neural stem cell lines derived from patients to produce intracranial xenograft syngraft tumors immunodeficient (NSG) or immunocompetent (C57BL/6) mice, respectively. High-parameter flow cytometry was compartment each model. investigated tissues brain, spleen, lymph node, bone marrow frequencies monocytes, macrophages, B cells, T dendritic neutrophils, eosinophils, where possible, their subsets. Results In a study first non-tumor-bearing we show dramatic differences between NSG C57BL/6 mice numbers not only cells but also cells. Then bearing significant draining nodes, spleen marrow. Also, effects on luciferase-expressing compared parental lines. Finally, whole-body irradiation numbers. Conclusions Our quantitative characterization models xenografts syngrafts allow better informed selection are appropriate pre-clinical investigation immunotherapies glioblastoma.

Language: Английский

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Autologous tumor lysate-loaded dendritic cell vaccination in glioblastoma patients: a systematic review of literature

Clinical & Translational Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Language: Английский

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IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 3, 2024

Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), master regulator of type 1 conventional dendritic cell (cDC1) development, in syngeneic murine GBM model. We hypothesized that RRV-mediated delivery IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting (APCs) and thereby restore T-cell responses.

Language: Английский

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Revisiting glioblastoma classification through an immunological lens: A narrative review

Glioma, Journal Year: 2024, Volume and Issue: 7(2), P. 3 - 9

Published: April 1, 2024

Glioblastoma (GBM) is characterized by a high recurrence rate, significant heterogeneity, and poor prognosis. While there has been shift in recent years to focus on molecular phenotyping, are limited data regarding the relationship between immune milieu heterogeneous signatures GBM. Given success of immunotherapies other cancers such as non-small-cell lung cancer melanoma, concerted effort correlate compartment GBM tumor microenvironment clinical outcomes. The aim this narrative review establish role immunophenotyping classification. Major cell groups involve myeloid cells (e.g. myeloid-derived suppressor cells, tumor-associated macrophages microglia, neutrophils, dendritic cells), lymphocytes (e.g., T, natural killer, B-cells), stromal fibroblasts, pericytes, endothelial cells). Understanding relationships these different populations correlating their roles with current classification scheme described 2021 World Health Organization criteria may further elucidate patterns response, especially light advances new immunotherapies.

Language: Английский

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Interferon regulatory factor 8-driven reprogramming of the immune microenvironment enhances antitumor adaptive immunity and reduces immunosuppression in murine glioblastoma

Neuro-Oncology, Journal Year: 2024, Volume and Issue: 26(12), P. 2272 - 2287

Published: Aug. 8, 2024

Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), master regulator of type 1 conventional dendritic cell (cDC1) development, in syngeneic murine GBM model. We hypothesized that RRV-mediated delivery IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting and thereby restore T-cell responses.

Language: Английский

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