Immune cell dynamics deconvoluted by single-cell RNA sequencing in normothermic machine perfusion of the liver

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

Опубликована: Апрель 21, 2023

Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing understanding for the donor immune cell composition and its dynamic changes during NMP is essential. We aimed a comprehensive characterization of (sub)populations, trafficking cytokine release liver NMP. Single-cell transcriptome profiling human livers prior to, after transplantation shows abundance CXC chemokine receptor 1+/2+ (CXCR1+/CXCR2+) neutrophils, which significantly decreased This paralleled by large efflux passenger leukocytes with neutrophil predominance in perfusate. During NMP, neutrophils shift from pro-inflammatory state towards aged/chronically activated/exhausted phenotype, while anti-inflammatory/tolerogenic monocytes/macrophages are increased. herein describe dynamics repertoire, phenotypic shifts dominance potentially contribute to inflammatory response. Our findings may serve resource initiate future immune-interventional studies.

Язык: Английский

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SLC3A2 promotes tumor‐associated macrophage polarization through metabolic reprogramming in lung cancer

Cancer Science, Год журнала: 2023, Номер 114(6), С. 2306 - 2317

Опубликована: Фев. 16, 2023

Tumor-associated macrophages (TAMs) are one of the most abundant immunosuppressive cells in tumor microenvironment and possess crucial functions facilitating progression. Emerging evidence indicates that altered metabolic properties cancer support tumorigenic TAMs. However, mechanisms mediators underly cross-talk between TAMs remain largely unknown. In present study, we revealed high solute carrier family 3 member 2 (SLC3A2) expression lung patients was associated with poor prognosis. Knockdown SLC3A2 adenocarcinoma impaired M2 polarization a coculture system. Using metabolome analysis, identified knockdown metabolism changed multiple metabolites, including arachidonic acid, microenvironment. More importantly, showed acid responsible for SLC3A2-mediated macrophage to differentiate into type both vitro vivo. Our data illustrate previously undescribed TAM suggest acts as switch on induce phenotypic reprogramming through acid.

Язык: Английский

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C1q⁺tumor-associated macrophages contribute to immunosuppression through fatty acid metabolic reprogramming in malignant pleural effusion

Journal for ImmunoTherapy of Cancer, Год журнала: 2023, Номер 11(8), С. e007441 - e007441

Опубликована: Авг. 1, 2023

Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as dominant population, impede antitumor response; however, underlying mechanisms have not been fully elucidated yet.Single-cell RNA sequencing analysis was performed portray macrophage landscape and revealed mechanism component 1q (C1q)+ TAMs. Malignant pleural effusion (MPE) human mouse used explore phenotypes functions C1q+ TAMs.C1q+ TAMs highly expressed multiple inhibitory molecules their high infiltration significantly correlated poor prognosis. promote MPE immunosuppression through impairing effects CD8+ T Mechanistically, enhance fatty acid binding protein 5 (FABP5)-mediated metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing gene expression molecules. A high-fat diet increases microenvironment, whereas low-fat ameliorates these effects. Moreover, FABP5 inhibition represses tumor progression, while enhancing efficacy ICB lung cancer.C1q+ cells promoting immunosuppression. Targeting effectively alleviates enhances therapy. great potential be therapeutic target for immunotherapy.

Язык: Английский

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Complement: The Road Less Traveled

The Journal of Immunology, Год журнала: 2023, Номер 210(2), С. 119 - 125

Опубликована: Янв. 3, 2023

Abstract The complement field has recently experienced a strong resurgence of interest because the unexpected discovery new functions extending complement’s role beyond immunity and pathogen clearance, growing list diseases in which plays role, proliferation therapeutics. Importantly, although majority components circulation are generated by liver activated extracellularly, activation unexpectedly also occurs intracellularly across broad range cells. Such cell-autonomous can engage intracellular receptors, then drive noncanonical cell-specific effector functions. Thus, much remains to be discovered about biology. In this brief review, we focus on novel activities its “classic areas operation” (kidney brain biology, infection, autoimmunity), with an outlook next generation complement-targeted

Язык: Английский

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Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 8, 2024

Abstract Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies DLBCL, and does not provide a comprehensive analysis macrophage subtypes. Here, using digital spatial profiling with whole transcriptome CD68+ cells, we characterize macrophages distinct niches reactive lymphoid tissues (RLTs) DLBCL. We reveal transcriptomic differences between within RLTs (light zone /dark zone, germinal center/ interfollicular), disease states (RLTs/ DLBCL), which then use to generate six spatially-derived signatures (MacroSigs). proceed interrogate these MacroSigs DLBCL single-cell RNA-sequencing datasets, gene-expression data from multiple cohorts. show that specific associated cell-of-origin subtypes overall survival This study provides spatially-resolved whole-transcriptome atlas malignant tissues, showing biological clinical significance.

Язык: Английский

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Advanced insights on tumor-associated macrophages revealed by single-cell RNA sequencing: The intratumor heterogeneity, functional phenotypes, and cellular interactions

Cancer Letters, Год журнала: 2024, Номер 584, С. 216610 - 216610

Опубликована: Янв. 19, 2024

Язык: Английский

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Revealing the role of SPP1+ macrophages in glioma prognosis and therapeutic targeting by investigating tumor-associated macrophage landscape in grade 2 and 3 gliomas

Cell & Bioscience, Год журнала: 2024, Номер 14(1)

Опубликована: Март 21, 2024

Abstract Background Glioma is a highly heterogeneous brain tumor categorized into World Health Organization (WHO) grades 1–4 based on its malignancy. The suppressive immune microenvironment of glioma contributes significantly to unfavourable patient outcomes. However, the cellular composition and their complex interplays within environment remain poorly understood, reliable prognostic markers elusive. Therefore, in-depth exploration (TME) identification predictive are crucial for improving clinical management patients. Results Our analysis single-cell RNA-sequencing data from samples unveiled immunosuppressive role tumor-associated macrophages (TAMs), mediated through intricate interactions with cells lymphocytes. We also discovered heterogeneity TAMs, among which group TAMs named TAM-SPP1 demonstrated significant association Epidermal Growth Factor Receptor ( EGFR ) amplification, impaired T cell response survival Furthermore, by leveraging genomic transcriptomic Cancer Genome Atlas (TCGA) dataset, two distinct molecular subtypes different constitution status outcomes were identified. Exploiting differences between these subtypes, we developed four-gene-based model. This model displayed strong associations an elevated level could be used predict anti-tumor prognosis in Conclusion findings illuminated mechanisms that shape gliomas, providing novel insights potential therapeutic targets. holds promise predicting immunotherapy assisting more precise risk stratification Graphical abstract

Язык: Английский

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Inside-Out of Complement in Cancer

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Июль 1, 2022

The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that accelerates progression. Despite pivotal fighting microbes, seems to suppress antitumor immunity via regulation host cell tumor microenvironment. Although most link activation extracellular space, discovery intracellular complement, raises question: what is relevance this process for malignancy? Intracellular survival immune cells. Therefore, can be important and growth regardless immunosuppression. On other hand, because (the complosome) indispensable T cells, these functions will essential priming responses. Here, we review with consideration extra pathways spatial distribution proteins tumors periphery our take on potential significance as biomarker target therapy.

Язык: Английский

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Complement activation in cancer: Effects on tumor-associated myeloid cells and immunosuppression

Seminars in Immunology, Год журнала: 2022, Номер 60, С. 101642 - 101642

Опубликована: Март 1, 2022

Язык: Английский

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Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1

Science Immunology, Год журнала: 2023, Номер 8(89)

Опубликована: Ноя. 17, 2023

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the compartment as a therapeutic vulnerability mouse models of pancreatic cancer. solid tumors expressed receptors including pattern recognition receptor Dectin-1 TNF superfamily member CD40. In checkpoint inhibitor-resistant cancer, coactivation Dectin-1, via systemic β-glucan therapy, CD40, with agonist antibody treatment, eradicated established induced immunological memory. Antitumor activity was dependent on cDC1s but did not require classical cell-mediated cytotoxicity or blockade molecules. Rather, targeting CD40 drove IFN-γ signaling, which converged to program distinct macrophage subsets tumor responses. Thus, productive surveillance resistant inhibition can be invoked complementary signaling pathways.

Язык: Английский

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