Cancer organoids 2.0: modelling the complexity of the tumour immune microenvironment

Nature reviews. Cancer, Год журнала: 2024, Номер 24(8), С. 523 - 539

Опубликована: Июль 8, 2024

Язык: Английский

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Deciphering the performance of macrophages in tumour microenvironment: a call for precision immunotherapy

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Июнь 11, 2024

Abstract Macrophages infiltrating tumour tissues or residing in the microenvironment of solid tumours are known as tumour-associated macrophages (TAMs). These specialized immune cells play crucial roles growth, angiogenesis, regulation, metastasis, and chemoresistance. TAMs encompass various subpopulations, primarily classified into M1 M2 subtypes based on their differentiation activities. macrophages, characterized by a pro-inflammatory phenotype, exert anti-tumoural effects, while with an anti-inflammatory function protumoural regulators. highly versatile respond to stimuli from other constituents within (TME), such growth factors, cytokines, chemokines, enzymes. induce polarization towards one phenotype another, leading complex interactions TME components influencing both pro-tumour anti-tumour processes. This review comprehensively deeply covers literature origin well intricate interplay between TME, dual nature promoting pro- Moreover, delves primary pathways implicated macrophage polarization, examining diverse that regulate this process. role shaping functions macrophages. In addition, advantages limitations current clinical interventions reviewed, including enhancing TAM phagocytosis, inducing exhaustion, inhibiting recruitment, polarizing M1-like phenotype. conclusion, treatment strategies targeting precision medicine show promise, overcoming several obstacles is still necessary achieve accessible efficient immunotherapy.

Язык: Английский

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T cell exhaustion in malignant gliomas

Trends in cancer, Год журнала: 2023, Номер 9(4), С. 270 - 292

Опубликована: Янв. 20, 2023

Despite advances in understanding tumor biology, malignant gliomas remain incurable. While immunotherapy has improved outcomes other cancer types, comparable efficacy not yet been demonstrated for primary cancers of the central nervous system (CNS). T cell exhaustion, defined as a progressive decrease effector function, sustained expression inhibitory receptors, metabolic dysfunction, and distinct epigenetic transcriptional alterations, contributes to failure CNS. Herein, we describe recent drivers exhaustion glioma microenvironment. We discuss extrinsic intrinsic factors that contribute highlight potential avenues reversing this phenotype. Our ability directly target specific immunosuppressive brain would be major advance immunotherapy.

Язык: Английский

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Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy

Cancer Cell, Год журнала: 2024, Номер 42(6), С. 1032 - 1050.e10

Опубликована: Май 16, 2024

Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response, but knowledge on the exact contribution of each cell subset limited. We show that therapy-induced intratumoral CD8+ T cells recruited skewed late-stage activated M1-like macrophages, which were critical for effective control in two different murine models cancer immunotherapy. The summon these macrophages into their close vicinity via CCR5 signaling. Exposure non-polarized to supernatant lysate recapitulates tumoricidal phenotype vitro. transcriptomic signature also detected similar macrophage population present human tumors coincides clinical response checkpoint inhibitors. requirement functional co-operation between effector gives warning combinations broad macrophage-targeting strategies.

Язык: Английский

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Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 20, 2023

Abstract The codependency of cholesterol metabolism sustains the malignant progression glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent tumors induces phagocytic dysfunction monocyte-derived tumor-associated macrophages (TAMs), resulting disease progression. Manipulating efflux with apolipoprotein A1 (ApoA1), a reverse transporter, restores TAM phagocytosis reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis vivo-sorted TAMs further reveals ApoA1 mediates lipid-related metabolic remodeling lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, immunity elicits long-term tumor-specific immune surveillance. Our findings provide insight into mechanisms by impairs offer an immunometabolic approach to target disturbances GBM.

Язык: Английский

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Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy

Nature Immunology, Год журнала: 2024, Номер 25(4), С. 644 - 658

Опубликована: Март 19, 2024

Язык: Английский

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The role of tumor-associated macrophages in tumor immune evasion

Journal of Cancer Research and Clinical Oncology, Год журнала: 2024, Номер 150(5)

Опубликована: Май 7, 2024

Abstract Background Tumor growth is closely linked to the activities of various cells in tumor microenvironment (TME), particularly immune cells. During progression, circulating monocytes and macrophages are recruited, altering TME accelerating growth. These adjust their functions response signals from stromal Tumor-associated (TAMs), similar M2 macrophages, key regulators TME. Methods We review origins, characteristics, TAMs within This analysis includes mechanisms through which facilitate evasion promote metastasis. Additionally, we explore potential therapeutic strategies that target TAMs. Results instrumental mediating malignant behaviors. They release cytokines inhibit effector attract additional immunosuppressive primarily T cells, inducing exhaustion directly, influencing activity indirectly cellular interactions, or suppressing checkpoints. directly involved proliferation, angiogenesis, invasion, Summary Developing innovative tumor-targeted therapies immunotherapeutic currently a promising focus oncology. Given pivotal role evasion, several approaches have been devised them. include leveraging epigenetics, metabolic reprogramming, engineering repolarize TAMs, inhibiting recruitment activity, using as drug delivery vehicles. Although some these remain distant clinical application, believe future targeting will offer significant benefits cancer patients.

Язык: Английский

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Multiplex immunofluorescence and single‐cell transcriptomic profiling reveal the spatial cell interaction networks in the non‐small cell lung cancer microenvironment

Clinical and Translational Medicine, Год журнала: 2023, Номер 13(1)

Опубликована: Янв. 1, 2023

Abstract Background Conventional immunohistochemistry technologies were limited by the inability to simultaneously detect multiple markers and lack of identifying spatial relationships among cells, hindering understanding biological processes in cancer immunology. Methods Tissue slices primary tumours from 553 IA∼IIIB non‐small cell lung (NSCLC) cases stained multiplex immunofluorescence (mIF) assay for 10 markers, including CD4, CD38, CD20, FOXP3, CD66b, CD8, CD68, PD‐L1, CD133 CD163, evaluating amounts 26 phenotypes cells tumour nest stroma. StarDist depth learning model was utilised determine location based on mIF graphs. Single‐cell RNA sequencing (scRNA‐seq) four NSCLC conducted investigate putative interaction networks. Results Spatial proximity CD20+ B CD4+ T CD38+ ( r 2 = 0.41) observed, whereas distribution regulatory associated with decreased infiltration levels −0.45). Univariate Cox analyses identified closer between CD8+ predicted longer disease‐free survival (DFS). In contrast, CD133+ stem (CSCs), distances neutrophils, neutrophils correlated dismal DFS. Data scRNA‐seq further showed that spatially adjacent N1‐like could boost proliferation activation lymphocytes, neighbouring M2‐like macrophages negative effects. An immune‐related risk score (IRRS) system aggregating robust quantitative prognosticators high‐IRRS patients had significantly worse DFS than low‐IRRS ones (HR 2.72, 95% CI 1.87–3.94, p < .001). Conclusions We developed a framework analyse networks microenvironment, revealing architecture intricate interplays immune cells.

Язык: Английский

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Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target

Clinical and Translational Medicine, Год журнала: 2023, Номер 13(2)

Опубликована: Фев. 1, 2023

Abstract Background Dendritic cells (DCs) mediate divergent immune effects by activating T or negatively regulating the response to promote tolerance. They perform specific functions determined their tissue distribution and maturation state. Traditionally, immature semimature DCs were described have immunosuppressive effects, leading Nonetheless, recent research has demonstrated that mature can also suppress under certain circumstances. Main body Mature enriched in immunoregulatory molecules (mregDCs) emerged as a regulatory module across species tumour types. Indeed, distinct roles of mregDCs immunotherapy sparked interest researchers field single‐cell omics. In particular, these found be associated with positive favourable prognosis. Conclusion Here, we provide general overview latest most notable advances findings regarding basic features complex nonmalignant diseases microenvironment. We emphasise important clinical implications tumours.

Язык: Английский

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Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti–PD-1 in head and neck cancer

Science Immunology, Год журнала: 2023, Номер 8(87)

Опубликована: Сен. 8, 2023

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration anti-programmed death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the microenvironment (TME). However, mechanisms underlying dynamics antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, approaches to increase are lacking. In a phase 2 trial (NCT02296684), we observed that 45% treated two doses pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis 17,158 CD8

Язык: Английский

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