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Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

ABSTRACT: Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

PROVIDER: PRJNA733462 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14676727.fastq.gz	Fastqsanger.gz
	SRR14676728.fastq.gz	Fastqsanger.gz
	SRR14676729.fastq.gz	Fastqsanger.gz
	SRR14676730.fastq.gz	Fastqsanger.gz
	SRR14676731.fastq.gz	Fastqsanger.gz

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Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

Project description:Immunotherapy is revolutionizing cancer treatment but can trigger toxicities that remain poorly understood. Here, by comprehensively analyzing mouse models following anti-CD40 therapy, we found an interdependent induction of the cytokines IFN-g and IL-12, which caused inflammatory pathology in various tumor-free tissues. In the liver, Kupffer cells mediated toxicity by sensing lymphocyte-derived IFN-g and producing IL-12, highlighting the vulnerability of tissue-resident macrophages to promote toxicity when reacting to proinflammatory cues. Conversely, dendritic cells drove tumor control but were dispensable for toxicity. We further show that liver macrophages, IL-12, and IFN-g were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. Similar inflammatory pathways characterized immunotherapy-related adverse events in cancer patients. These findings implicate resident macrophages and neutrophils as mediators and effectors of aberrant inflammation, and suggest distinct cellular mechanisms of toxicity and antitumor immunity.

2021-06-03 | GSE175737 | GEO

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

Project description:Immunotherapy is revolutionizing cancer treatment, but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions remains poorly understood. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we show liver macrophages’ vulnerability to promote local adverse events. Mechanistically, tissue-resident Kupffer cells mediate liver toxicity by sensing lymphocyte-derived IFN-g and producing IL-12. Conversely, dendritic cells are dispensable for toxicity but drive tumor control. Though macrophages, IL-12, and IFN-g are not necessarily toxic themselves, we find that they prompt a neutrophil response that determines the severity of tissue damage. We further show that similar inflammatory pathways characterize adverse events across tissues, following anti-PD-1 and anti-CTLA4 immunotherapies, and in humans. These findings implicate macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, and suggest distinct mechanisms of toxicity and antitumor immunity.

2021-06-04 | GSE176109 | GEO

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

Project description:Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

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Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity

Project description:Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity

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Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity [Multiplexed_CD40]

Project description:Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity [Multiplexed_CD40]

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Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity [Ter119 experiment]

Project description:Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity [Ter119 experiment]

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Faecalibacterium prausnitzii abrogates immunotherapy toxicity

Project description:Faecalibacterium prausnitzii abrogates immunotherapy toxicity

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Gene expression in inflammatory macrophages, tissue resident macrophages and neutrophils

Project description:Genes expression in Ly6C+/F4/80+ inflammatory macrophages, CX3CR1+/F4/80+ tissue resident macrophages and Ly6G+/F4/80- neutrophils which were isolated from day 3 wounds in C57/B6 mice aged 8 weeks by cell sorting Ly6C+ macrophages expressed higher (over 5 folds) levels of 241 genes compared to CX3CR1+ macrophages, and 3382 genes compared to neutrophils

2016-07-01 | E-GEOD-74783 | biostudies-arrayexpress

ATAC-seq of tissue resident neutrophils

Project description:ATAC-seq of tissue resident neutrophils

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Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury

Project description:Molecular profiling of infiltrating monocyte-derived macrophages versus resident kupffer cells following acute liver injury The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF-subsets. Here, we utilized a murine model of acute liver injury caused by overdose of acetaminophen (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP-challenge and started recovering by self-renewal at resolution phase without contribution of circulating Ly6Chi monocytes. The latter were recruited in a CCR2 and M-CSF mediated pathway at the necro-inflammatory phase and differentiated into ephemeral Ly6Clo MF subset at resolution phase. Moreover, their inducible ablation resulted in impaired recovery. Microarray based molecular profiling uncovered high similarity between steady state KC and those recovered at the resolution phase. In contrast, KC and monocyte-derived MF displayed distinct pro-restorative genetic signature at the resolution phase. Finally, we show that infiltrating monocytes acquire a pro-restorative polarization manifested by unique expression of pro-angiogenesis mediators and genes involved with inhibition of neutrophil activity and recruitment and promotion of their clearance. Collectively, our results present a novel phenotypic, ontogenic and molecular definition of liver-MF compartment following acute injury. 11 Samples (arrays) were performed. We generated pairwise comparison between all the different macrophages stages, using Partek Genomics Suite. Genes with p?5%[FDR] and a fold-change difference of ?2 or <-2 were selected.

2014-08-01 | E-GEOD-55606 | biostudies-arrayexpress

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