Trends in Pharmacological Sciences, Journal Year: 2022, Volume and Issue: 43(8), P. 686 - 700
Published: May 7, 2022
Language: Английский
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
Citations
187
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
Citations
62
Cell Reports, Journal Year: 2023, Volume and Issue: 42(2), P. 112127 - 112127
Published: Feb. 1, 2023
Glioblastoma (GBM) is one of the most aggressive tumors in adult central nervous system. We previously revealed that circadian regulation glioma stem cells (GSCs) affects GBM hallmarks immunosuppression and GSC maintenance a paracrine autocrine manner. Here, we expand mechanism involved angiogenesis, another critical hallmark, as potential basis underlying CLOCK's pro-tumor effect GBM. Mechanistically, CLOCK-directed olfactomedin like 3 (OLFML3) expression results hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation periostin (POSTN). As result, secreted POSTN promotes tumor angiogenesis via activation TANK-binding kinase 1 (TBK1) signaling endothelial cells. In mouse patient-derived xenograft models, blockade POSTN-TBK1 axis inhibits progression angiogenesis. Thus, CLOCK-POSTN-TBK1 circuit coordinates key tumor-endothelial cell interaction represents an actionable therapeutic target for
Language: Английский
Citations
46
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: March 5, 2024
Abstract Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs migration lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling functional studies demonstrate A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer activator transcription 3 (STAT3) transcriptional co-activators in cells to upregulate C-C motif chemokine ligand 2 (CCL2) CCL7, which recruit macrophages into microenvironment. Reciprocally, infiltrating produce LDHA-containing vesicles promote glycolysis, proliferation, survival. Genetic pharmacological inhibition LDHA-mediated tumor-macrophage symbiosis markedly suppresses progression mouse models. Analysis plasma samples patients confirms LDHA its downstream signals potential biomarkers correlating positively with density. Thus, provides therapeutic targets for
Language: Английский
Citations
39
Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(12), P. 1354 - 1375
Published: Oct. 15, 2024
Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard care offers minimal clinical benefit, most GBM patients experience recurrence after treatment. In recent years, significant advancements have been made the development novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance many advanced cancers. However, benefit immune-based treatments limited because unique immune profiles, cell heterogeneity, immunosuppressive microenvironment. this review, we present a detailed overview current immunotherapeutic discuss challenges potential molecular mechanisms underlying GBM. Furthermore, provide in-depth discussion regarding GBM, which will likely require combination therapies.
Language: Английский
Citations
22
Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)
Published: March 13, 2024
Abstract Tissue-resident macrophages play an important role in the local maintenance of homeostasis and immune surveillance. In central nervous system (CNS), brain are anatomically divided into parenchymal microglia non-parenchymal border-associated (BAMs). Among these cell populations, have been well-studied for their roles during development as well health disease. BAMs, mostly located choroid plexus, meningeal perivascular spaces, now gaining increased attention due to advancements multi-omics technologies genetic methodologies. Research on BAMs over past decade has focused ontogeny, immunophenotypes, involvement various CNS diseases, potential therapeutic targets. Unlike microglia, display mixed origins distinct self-renewal capacity. believed regulate neuroimmune responses associated with barriers contribute immune-mediated neuropathology. Notably, observed function diverse cerebral pathologies, including Alzheimer’s disease, Parkinson’s multiple sclerosis, ischemic stroke, gliomas. The elucidation heterogeneity functions neuroinflammation is mesmerizing, since it may shed light precision medicine that emphasizes deep insights programming cues unique microenvironment. this review, we delve latest findings covering aspects like origins, capacity, adaptability, implications different disorders.
Language: Английский
Citations
20
Trends in Cell Biology, Journal Year: 2021, Volume and Issue: 31(11), P. 940 - 950
Published: July 13, 2021
Language: Английский
Citations
74
Cancer Immunology Research, Journal Year: 2022, Volume and Issue: 10(6), P. 770 - 784
Published: April 12, 2022
Abstract The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for progression. However, molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) its heterodimeric partner brain muscle ARNT-like 1 (BMAL1) glioma (GSC) drive immunosuppression GBM. Integrated analyses of data from transcriptome profiling, single-cell RNA sequencing, TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target CLOCK–BMAL1 complex GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN GSCs via hypoxia-inducible factor 1-alpha (HIF1α) signaling. Consequently, promotes microglial infiltration into GBM TME upregulating CD162 polarizes infiltrating microglia toward an immune-suppressive phenotype. In mouse models, inhibition CLOCK–OLFML3–HIF1α–LGMN–CD162 axis reduces intratumoral microglia, increases CD8+ T-cell infiltration, activation, cytotoxicity, synergizes anti–programmed cell death protein (anti–PD-1 therapy). human GBM, CLOCK-regulated signaling correlates positively abundance poor prognosis. Together, these findings uncover CLOCK–OLFML3–HIF1α–LGMN switch controls biology immunosuppression, thus revealing potential new therapeutic targets patients
Language: Английский
Citations
66
Cancers, Journal Year: 2022, Volume and Issue: 14(5), P. 1319 - 1319
Published: March 4, 2022
Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent malignant one. The highly infiltrative nature gliomas, their intrinsic intra- intertumoral heterogeneity, pose challenges towards developing effective treatments. glioma microenvironment, in addition, also thought play critical role during tumor development treatment course. Unlike other solid tumors, microenvironment dominated by macrophages microglia-collectively known tumor-associated (TAMs). TAMs, like homeostatic counterparts, are plastic can polarize either pro-inflammatory or immunosuppressive states. Many lines evidence suggest that TAMs dominate fosters development, contributes aggressiveness recurrence and, very importantly, impedes therapeutic effect various regimens. However, through new strategies, potentially be shifted proinflammatory state great interest. In this review, we will discuss aspects context glioma. focus on basic biology central nervous system (CNS), potential biomarkers, evaluation model systems for studying finally, special attention given targeted options involve TAM compartment gliomas.
Language: Английский
Citations
64
Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 20
Published: Aug. 22, 2022
Hypoxia-induced M2 phenotypes of tumor associated macrophages (TAMs) promote the development and chemoresistance multiple types cancers, including glioblastoma (GBM). However, detailed molecular mechanisms have not been fully understood. In this study, we firstly reported that hypoxic pressure promoted macrophage generation, which further cancer progression temozolomide (TMZ) resistance in GBM through secreting vascular endothelial growth factor (VEGF). Specifically, clinical data suggested were significantly enriched tissues compared with adjacent normal tissues, following vitro experiments validated M2-polarized upregulating hypoxia-inducible factor-1α (HIF-1α). addition, VEGF-dependently cell proliferation, epithelial-mesenchymal transition (EMT), stem (GSC) properties, TMZ cells activating PI3K/Akt/Nrf2 pathway. Also, secreted VEGF to accelerate angiogenesis human umbilical vein (HUVECs) interacting its receptor VEGFR. general, concluded contributed progression, stemness, drug resistance, VEGF, our supported notion targeting hypoxia-associated might be an effective treatment strategy for practices.
Language: Английский
Citations
41