Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 28, 2023

Abstract Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel LAG-3 drugs have also been approved clinical application. With the widespread use of drug, we must deeply analyze dilemma agents seek a breakthrough treatment prospect. Over past decades, these demonstrated dramatic efficacy, especially patients with melanoma non-small cell lung cancer (NSCLC). Nonetheless, field broad concept solid tumours, non-specific indications, inseparable immune response side effects, unconfirmed progressive disease, complex regulatory networks resistance are four barriers that limit its Fortunately, successful trials ICB combination therapies, advent era oncolytic virus gene editing, technical mRNA vaccines nano-delivery systems made remarkable breakthroughs currently. In this review, enumerate mechanisms each checkpoint targets, associations between tumour mutation burden, key or signalling pathways, specific evidence efficacy classical targets new among different types put forward dialectical thoughts on drug safety. Finally, discuss importance accurate triage based recent advances predictive biomarkers diagnostic testing techniques.

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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Beyond T cell exhaustion: TIM-3 regulation of myeloid cells

Science Immunology, Journal Year: 2024, Volume and Issue: 9(93)

Published: March 8, 2024

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an important immune checkpoint molecule initially identified as a marker of IFN-γ–producing CD4 + CD8 cells. Since then, our understanding its role in responses has significantly expanded. Here, we review emerging evidence demonstrating unexpected roles for TIM-3 key regulator myeloid function, addition to recent work establishing delineator terminal exhaustion, thereby positioning at the interface between fatigued reinvigoration. We share perspective on antagonism stemness, discussing both cell-intrinsic cell-extrinsic mechanisms underlying this relationship. Looking forward, discuss approaches decipher by which regulates remarkable potential treatment cancer, autoimmunity, autoinflammation.

Language: Английский

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Role of the AKT signaling pathway in regulating tumor-associated macrophage polarization and in the tumor microenvironment: A review

Medicine, Journal Year: 2025, Volume and Issue: 104(5), P. e41379 - e41379

Published: Jan. 31, 2025

Tumor-associated macrophages (TAMs) are present in and important components of the tumor microenvironment (TME). TAMs differentiate into 2 functionally distinct morphologies, classically activated (M1)-type alternatively (M2)-type TAMs, when stimulated by different cytokines. The types exhibit properties functions. M1 secrete high levels pro-inflammatory chemotactic factors, exerting proinflammatory, antitumor effects. Conversely, M2 alter extracellular matrix, facilitate cellular immune escape, stimulate angiogenesis, thereby promoting anti-inflammatory responses growth. ratio to TME is closely related prognosis tumor. Tumor cells other can regulate polarization thus promote progression through secretion various substances; however, polarized also act on exosomes, forming a positive feedback loop. Therefore, modulating phenotype or blocking might be new approach for cancer treatment. However, intracellular signaling pathways involved poorly understood. AKT pathway an polarization, growth, proliferation, recruitment, apoptosis as well action within TME. This paper reviews regulation provides ideas immunotherapy.

Language: Английский

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Single‐cell RNA sequencing reveals tumor heterogeneity, microenvironment, and drug‐resistance mechanisms of recurrent glioblastoma

Cancer Science, Journal Year: 2023, Volume and Issue: 114(6), P. 2609 - 2621

Published: Feb. 28, 2023

Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, remains refractory to recurrence is inevitable. Moreover, biology recurrent unclear. Increasing evidence has shown that intratumoral heterogeneity tumor microenvironment contribute therapeutic resistance. However, interaction between intracellular drug resistance in GBMs controversial. The aim this study was map transcriptome landscape cancer cells drug-resistant at a single-cell resolution further explore mechanism GBMs. We analyzed six tissue samples from three patients with primary GBM developed after protocol using RNA sequencing. Using unbiased clustering, nine major cell clusters were identified. Upregulation expression stemness-related cell-cycle-related genes observed cells. Compared initial tissues, tissues showed decreased proportion microglia, consistent previous reports. Finally, vascular endothelial growth factor A blood-brain barrier permeability high, O6 -methylguanine DNA methyltransferase-related signaling pathway activated GBM. Our results delineate glioblastoma, heterogeneity, microenvironment, drug-resistance mechanisms, providing new insights into strategies glioblastomas.

Language: Английский

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Tumor-associated macrophage-related strategies for glioma immunotherapy

npj Precision Oncology, Journal Year: 2023, Volume and Issue: 7(1)

Published: Aug. 19, 2023

Abstract High-grade glioma is one of the deadliest primary tumors central nervous system. Despite many novel immunotherapies currently in development, it has been difficult to achieve breakthrough results clinical studies. The reason may be due suppressive tumor microenvironment gliomas that limits function specific immune cells (e.g., T cells) which are targets immunotherapy. However, tumor-associated macrophage, enriched tumors, plays an important role development GBM and becoming a research hotspot for This review focuses on current advances use macrophages as therapeutic or tools gliomas, provides some potential directions.

Language: Английский

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The multiple roles of interferon regulatory factor family in health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 9, 2024

Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores diverse functions nine mammalian IRF members, each featuring conserved domains essential for interactions with other factors cofactors. These allow IRFs to modulate broad spectrum processes, encompassing host defense, response, cell development. Conversely, their pivotal role in regulation implicates them pathophysiology various diseases, such as infectious autoimmune disorders, metabolic cancers. In this context, display dichotomous nature, functioning tumor suppressors promoters, contingent upon specific disease milieu. Post-translational modifications IRFs, including phosphorylation ubiquitination, play crucial modulating function, stability, activation. As prospective biomarkers therapeutic targets, present promising opportunities intervention. Further research is needed elucidate precise mechanisms governing regulation, potentially pioneering innovative strategies, particularly cancer treatment, where equilibrium activities paramount importance.

Language: Английский

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IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy

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

Published: Jan. 5, 2024

Background Glioma is the prevailing malignant intracranial tumor, characterized by an abundance of macrophages. Specifically, infiltrating macrophages often display M2 subtype and are known as tumor-associated (TAMs). They have a critical role in promoting oncogenic properties tumor cells. Interleukin-4-induced-1 (IL4I1) functions L-phenylalanine oxidase, playing key part regulating immune responses progression various tumors. However, there limited understanding IL4I1-mediated cross-talk function between TAMs glioma cell microenvironment. Methods TCGA, GTEx, HPA databases were applied to assess IL4I1 expression, clinical characteristics, prognostic value pan-cancer. The link levels prognosis, methylation, checkpoints (ICs) gliomas explored through Kaplan–Meier curve, Cox regression, Spearman correlation analyses. their distribution investigated single-cell analysis TIMER 2 database. Additionally, validation expression was performed WB, RT-qPCR, IHC, IF. Co-culture models cells M2-like used explore effects on growth, invasion, migration Moreover, macrophage polarization evaluated ELISA, siRNA transfection. Results Both transcriptome protein increased obviously types, correlated with dismal prognosis. implicated aggressive prognosis for patients glioma. A negative association noticed grade DNA promoter methylation IL4I1. Enrichment analyses suggested that linked cytokine responses, positively ICs. Single-cell analysis, molecular experiments, vitro assays showed significantly expressed TAMs. Importantly, co-culture proved promoted invasion cells, induced Conclusion could be promising immunotherapy target selective modulation stands novel macrophage-related biomarker

Language: Английский

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Macrophage plasticity and function in cancer and pregnancy

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

Published: Jan. 11, 2024

As the soil of life, composition and shaping process immune microenvironment uterus is worth exploring. Macrophages, indispensable constituents innate system, are essential mediators inflammation tissue remodeling as well. Recent insights into heterogeneity macrophage subpopulations have renewed interest in their functional diversity both physiological pathological settings. Macrophages display remarkable plasticity switch from one phenotype to another. Intrinsic enables macrophages perform a variety functions response changing contexts, such cancer pregnancy. The make particularly intriguing cells given dichotomous role either attacking or protecting tumors semi-allogeneic fetuses, which characterized functionally by immunomodulation neovascularization. Here, we reviewed compared novel perspectives on biology these two settings, including origin, phenotype, differentiation, roles corresponding microenvironments, informed recent studies identity function, well mechanisms that might offer opportunities for new therapeutic strategies malignancy pregnancy complications.

Language: Английский

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Myeloid cells as potential targets for immunotherapy in pediatric gliomas

Frontiers in Pediatrics, Journal Year: 2024, Volume and Issue: 12

Published: March 8, 2024

Pediatric high-grade glioma (pHGG) including pediatric glioblastoma (pGBM) are highly aggressive central nervous system (CNS) malignancies. pGBM comprises approximately 3% of all CNS malignancies and has a 5-year survival rate 20%. Surgical resection chemoradiation often the standard care for pHGG, however, even with these interventions, children diagnosed pHGG remains poor. Due to shortcomings associated care, many efforts have been made create novel immunotherapeutic approaches targeted These include use vaccines, cell-based therapies, immune-checkpoint inhibitors. However, it is believed that in patients an immunosuppressive tumor microenvironment (TME) possess barriers limit efficacy immune-based therapies. One includes presence myeloid cells. In this review we will discuss various types cells present TME, macrophages microglia, myeloid-derived suppressor cells, dendritic as well specific mechanisms can employ enable immunosuppression. Finally, highlight therapeutic strategies aimed at impeding myeloid-cell derived

Language: Английский

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