Immune checkpoint therapy—current perspectives and future directions

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1652 - 1669

Published: April 1, 2023

Language: Английский

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Applications of single-cell RNA sequencing in drug discovery and development

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 496 - 520

Published: April 28, 2023

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery development. New opportunities emerging in target identification owing to improved disease understanding through cell subtyping, highly multiplexed functional genomics screens incorporating scRNA-seq enhancing credentialling prioritization. ScRNA-seq is also aiding selection relevant preclinical models providing new insights into mechanisms action. In clinical development, can inform decision-making via biomarker for patient stratification more precise monitoring response progression. Here, we illustrate how methods being applied key steps discuss ongoing challenges their implementation pharmaceutical industry. There have been significant recent advances development remarkable Ferran colleagues primarily pipeline, from decision-making. Ongoing potential future directions discussed.

Language: Английский

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Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(1)

Published: Jan. 2, 2023

Glioblastoma (GBM) is the most aggressive tumor in central nervous system and contains a highly immunosuppressive microenvironment (TME). Tumor-associated macrophages microglia (TAMs) are dominant population of immune cells GBM TME that contribute to hallmarks, including immunosuppression. The understanding TAMs has been limited by lack powerful tools characterize them. However, recent progress on single-cell technologies offers an opportunity precisely at level identify new TAM subpopulations with specific tumor-modulatory functions GBM. In this Review, we discuss heterogeneity plasticity summarize current TAM-targeted therapeutic potential We anticipate use followed functional studies will accelerate development novel effective therapeutics for patients.

Language: Английский

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Glioblastoma heterogeneity at single cell resolution

Oncogene, Journal Year: 2023, Volume and Issue: 42(27), P. 2155 - 2165

Published: June 5, 2023

Language: Английский

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Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective

Cell, Journal Year: 2024, Volume and Issue: 187(2), P. 446 - 463.e16

Published: Jan. 1, 2024

Language: Английский

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Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: May 8, 2024

Abstract Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, exploration of emerging modalities such as immunotherapy integration medicine engineering technology therapy, efficacy these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny inhibitory milieu within GBM has underscored significance cellular constituents microenvironment their interactions with cells neurons. Novel immune targeted therapy strategies have emerged, offering promising avenues for advancing treatment. One pivotal mechanism orchestrating immunosuppression involves aggregation myeloid-derived suppressor (MDSCs), glioma-associated macrophage/microglia (GAM), regulatory T (Tregs). Among these, MDSCs, though constituting minority (4–8%) CD45 + GBM, play central component fostering evasion propelling tumor progression, angiogenesis, invasion, metastasis. MDSCs deploy intricate mechanisms that adapt dynamic (TME). Understanding interplay between provides compelling basis This review seeks elucidate inherent explore existing targets, consolidate insights into MDSC induction contribution immunosuppression. Additionally, comprehensively surveys ongoing clinical trials potential strategies, envisioning future where targeting could reshape landscape GBM. Through synergistic other modalities, this approach can establish multidisciplinary, multi-target paradigm, ultimately improving prognosis quality life patients

Language: Английский

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CTLA-4 blockade induces a microglia-Th1 cell partnership that stimulates microglia phagocytosis and anti-tumor function in glioblastoma

Immunity, Journal Year: 2023, Volume and Issue: 56(9), P. 2086 - 2104.e8

Published: Aug. 11, 2023

Language: Английский

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Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma

Immunity, Journal Year: 2024, Volume and Issue: 57(5), P. 1105 - 1123.e8

Published: May 1, 2024

Language: Английский

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Glioblastoma Microenvironment and Invasiveness: New Insights and Therapeutic Targets

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 7047 - 7047

Published: April 11, 2023

Glioblastoma (GBM) is the most common and malignant primary brain cancer in adults. Without treatment mean patient survival approximately 6 months, which can be extended to 15 months with use of multimodal therapies. The low effectiveness GBM therapies mainly due tumor infiltration into healthy tissue, depends on cells’ interaction microenvironment (TME). cells TME involves cellular components such as stem-like cells, glia, endothelial non-cellular extracellular matrix, enhanced hypoxia, soluble factors adenosine, promote GBM’s invasiveness. However, here we highlight role 3D patient-derived glioblastoma organoids cultures a new platform for study modeling In this review, mechanisms involved GBM-microenvironment are described discussed, proposing potential prognosis biomarkers therapeutic targets.

Language: Английский

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Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(5), P. 815 - 832.e12

Published: April 18, 2024

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic cues acquire hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions activating adrenomedullin paracrine signaling, thereby stimulating hyperpermeable neovasculature hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation pharmacological blockade produced restores vascular integrity, improves intratumoral concentration anti-tumor agent dabrafenib, achieves combinatorial therapeutic benefits. Increased proportion expression predictive tumor vessel hyperpermeability worse prognosis glioblastoma. Our findings highlight diversity spatial niche-steered reprogramming indicate potential therapeutics targeting normalize vasculature.

Language: Английский

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