Systemic and local immunosuppression in glioblastoma and its prognostic significance DOI Creative Commons
Aleksei A. Stepanenko, Anastasiia O. Sosnovtseva, M. P. Valikhov

et al.

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

The promising role of tumor-associated macrophages in the treatment of cancer DOI
Hongbin Wang, Xueying Wang, Xin Zhang

et al.

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 73, P. 101041 - 101041

Published: Jan. 3, 2024

Language: Английский

Citations

59
Examining the function of macrophage oxidative stress response and immune system in glioblastoma multiforme through analysis of single-cell transcriptomics DOI Creative Commons
Xing Jin,

Huabao Cai,

Zhiheng Lin

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 11, 2024

Background Glioblastoma (GBM), a prevalent malignant neoplasm within the neuro-oncological domain, has been subject of considerable scrutiny. Macrophages, serving as principal immunological constituents, profoundly infiltrate microenvironment GBM. However, investigations elucidating intricate mechanisms governing macrophage involvement in GBM at single-cell level remain notably limited. Methods We conducted comprehensive investigation employing analysis, aiming to redefine cellular landscape both core and peripheral regions tumors. Our analytical focus extended profound study macrophages, their roles context oxidative stress, intercellular information exchange, trajectories concerning its assorted subpopulations. pursued identification prognostic genes intricately associated with macrophages. Utilizing experimental research investigate relevance MANBA Results have illuminated central role macrophages interplay among various subpopulations microenvironment. Notably, we observed pronounced intensity stress responses when compared counterparts other Moreover, orchestrated communication networks, facilitated by SPP1-CD44 axis, internally neighboring These findings collectively suggest potential for polarization from an M1 M2 phenotype, contributing immune suppression tumor Furthermore, our exploration unearthed closely most TCF12. Remarkably, appears participate modulation neuroimmune functionality exerting inhibitory effects on M1-polarized thereby fostering progression. To bolster these assertions, validations unequivocally affirmed promotional impact GBM, elucidated through capacity curb cell proliferation, invasiveness, metastatic potential. Conclusion revelations represent pivotal step towards unraveling interactions between diverse milieu. they lay foundation development innovative model, epicenter, underscore novel immunotherapeutic targets ongoing pursuit enhanced treatment modalities this formidable malignancy.

Language: Английский

Citations

51
Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation DOI Creative Commons
Ting Sun, Bin Liu, Yanyan Li

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Sept. 29, 2023

Abstract Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of inducing the formation microenvironment remains be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed orthotopic xenografts nude mice using flow cytometry assay immunohistochemical staining after oxamate, a dehydrogenase A (LDHA) inhibitor, control T or cells injection alone combination. RT-qPCR, western blot, cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation ELISA performed measure effect on regulation CD39, CD73 CCR8 cultured glioma stem cells, CD4 + macrophages. Results Oxamate promoted immune activation tumor-infiltrating through altering phenotypes molecules increasing regulatory (Treg) infiltration glioblastoma mouse model. Lactate accumulation within upregulated expressions both lactate-treated cells-co-cultured macrophages, intracellular directly elevated activities these gene promotors histone H3K18 lactylation. Conclusions Utilizing generation inhibitor not only reprogramed glucose metabolism cancer but also alleviated immunosuppression reduced CAR-Treg which may potential strategy enhance function therapy.

Language: Английский

Citations

49
Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma DOI Creative Commons
Lizhi Pang, Madeline Dunterman, Wenjing Xuan

et al.

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

48
Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression DOI Creative Commons
Fatima Khan, Yiyun Lin, Heba Ali

et al.

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

46
Glioblastoma vaccines: past, present, and opportunities DOI Creative Commons
Zujian Xiong, Itay Raphael, Michael R. Olin

et al.

EBioMedicine, Journal Year: 2024, Volume and Issue: 100, P. 104963 - 104963

Published: Jan. 5, 2024

Glioblastoma (GBM) is one of the most lethal central nervous systems (CNS) tumours in adults. As supplements to standard care (SOC), various immunotherapies improve therapeutic effect other cancers. Among them, tumour vaccines can serve as complementary monotherapy or boost clinical efficacy with immunotherapies, such immune checkpoint blockade (ICB) and chimeric antigen receptor T cells (CAR-T) therapy. Previous studies GBM have suggested that few neoantigens could be targeted due low mutation burden, single-peptide vaccination had limited control monotherapy. Combining diverse antigens, including neoantigens, tumour-associated antigens (TAAs), pathogen-derived optimizing vaccine design strategy may help improvement. In this review, we discussed current platforms, evaluated potential antigenic targets, challenges, perspective opportunities for

Language: Английский

Citations

34
Immunotherapy for glioblastoma: current state, challenges, and future perspectives DOI Creative Commons
Yang Liu, Zhou Fei, Heba Ali

et al.

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

30
Decoding the spatiotemporal heterogeneity of tumor-associated macrophages DOI Creative Commons

Xiangyuan Chu,

Yu Tian, Chao Lv

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: July 27, 2024

Abstract Tumor-associated macrophages (TAMs) are pivotal in cancer progression, influencing tumor growth, angiogenesis, and immune evasion. This review explores the spatial temporal heterogeneity of TAMs within microenvironment (TME), highlighting their diverse subtypes, origins, functions. Advanced technologies such as single-cell sequencing multi-omics have elucidated intricate interactions between other TME components, revealing mechanisms behind recruitment, polarization, distribution. Key findings demonstrate that support vascularization, promote epithelial-mesenchymal transition (EMT), modulate extracellular matrix (ECM) remodeling, etc., thereby enhancing invasiveness metastasis. Understanding these complex dynamics offers new therapeutic targets for disrupting TAM-mediated pathways overcoming drug resistance. underscores potential targeting to develop innovative therapies, emphasizing need further research into characteristics functional roles TME.

Language: Английский

Citations

28
Cathepsin B-Responsive Programmed Brain Targeted Delivery System for Chemo-Immunotherapy Combination Therapy of Glioblastoma DOI

Shaoping Jiang,

Wenpei Li,

Jun Yang

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(8), P. 6445 - 6462

Published: Feb. 15, 2024

Tumor-associated macrophages (TAMs) are closely related to the progression of glioblastoma multiform (GBM) and its development therapeutic resistance conventional chemotherapy. TAM-targeted therapy combined with chemotherapy has emerged as a promising strategy combat GBM. However, presence blood–brain barrier (BBB) severely limits efficacy. Meanwhile, lack ability distinguish different targeted cells also poses challenge for precise therapy. Herein, we propose cathepsin B (CTSB)-responsive programmed brain-targeted delivery system (D&R-HM-MCA) simultaneous GBM-targeted delivery. D&R-HM-MCA could cross BBB via low density lipoprotein receptor-associated protein 1 (LRP1)-mediated transcytosis. Upon reaching GBM site, outer angiopep-2 modification be detached from cleavage CTSB-responsive peptide, which circumvent abluminal LRP1-mediated efflux. The exposed p-aminophenyl-α-d-mannopyranoside (MAN) further recognize glucose transporter-1 (GLUT1) on macrophage mannose receptor (MMR) TAMs. achieve chemotherapeutic killing simultaneously induce TAM polarization anti-inflammatory M2 phenotype pro-inflammatory M1 phenotype, thus resensitizing response improving anti-GBM immune response. This not only can improve brain efficiency, but enable combination chemo-immunotherapy against effectiveness this may provide thinking designing more functional systems effective regimens.

Language: Английский

Citations

22
Lipid droplets in central nervous system and functional profiles of brain cells containing lipid droplets in various diseases DOI Creative Commons

Longxiao Zhang,

Yunfei Zhou, Zhongbo Yang

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 13, 2025

Lipid droplets (LDs), serving as the convergence point of energy metabolism and multiple signaling pathways, have garnered increasing attention in recent years. Different cell types within central nervous system (CNS) can regulate to generate or degrade LDs response diverse pathological stimuli. This article provides a comprehensive review on composition CNS, their generation degradation processes, interaction mechanisms with mitochondria, distribution among different types, roles played by these cells-particularly microglia astrocytes-in various prevalent neurological disorders. Additionally, we also emphasize paradoxical role post-cerebral ischemia inflammation explore potential underlying mechanisms, aiming identify novel therapeutic targets for this disease.

Language: Английский

Citations

3