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Systemic blockade of Clever-1 in patients with solid tumours elicits lymphocyte activation alongside checkpoint molecule downregulation

ABSTRACT: Systemic blockade of Clever-1 in patients with solid tumours elicits lymphocyte activation alongside checkpoint molecule downregulation

PROVIDER: PRJNA638546 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11973449.fastq.gz	Fastqsanger.gz
	SRR11973450.fastq.gz	Fastqsanger.gz
	SRR11973451.fastq.gz	Fastqsanger.gz
	SRR11973452.fastq.gz	Fastqsanger.gz
	SRR11973453.fastq.gz	Fastqsanger.gz

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Systemic blockade of Clever-1 in patients with solid tumours elicits lymphocyte activation alongside checkpoint molecule downregulation

Project description:Macrophages are critical in driving an immunosuppressive tumour microenvironment that counteracts the efficacy of T-cell targeting therapies1. Thus agents, which can re-programme macrophages towards a pro-inflammatory state hold promise as novel immunotherapies for solid cancers2. Here we report that therapeutic targeting of a macrophage scavenger receptor, Clever-13, in heavily pre-treated metastatic cancer patients was able to induce a significant increase and activation of peripheral T-cells including downregulation of several immune checkpoint molecules. Transcriptional and mass cytometry analyses revealed treatment induced inflammatory conversion of blood monocytes, which was partly driven by impaired Clever-1 mediated scavenging. Identification of relevant peripheral signatures indicative of anti-tumour activity showed induction of an effector CD8 T-cell population that resulted from clonal expansion of cytotoxic CD8 T-cells. In some patients this was accompanied by features of increased accumulation of CD8 T-cells in post-treatment tumour biopsies. Our results reveal a non-redundant role played by the receptor Clever-1 in suppressing adaptive immune cell activation in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch leading to peripheral activation and potentially intra tumoural proinflammatory responses in metastatic cancer patients. Anti-Clever-1 treatment may therefore provide an attractive immunotherapeutic strategy in cancer.

2022-05-22 | GSE152169 | GEO

Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors: Results from a Phase I/II Clinical Trial.

Project description:PurposeMacrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8+ T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment.Patients and methodsIn this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer.ResultsOur pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8+ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients.ConclusionsOur results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.

| S-EPMC9401456 | biostudies-literature

Specific endothelical cells govern nanoparticle entry into solid tumours

Project description:We sequenced the transcroptome of isolated nanoparticle positive and nanoparticle negative tumour endothelial cells from mouse 4T1 mammary tumours

2021-09-07 | GSE172496 | GEO

CREBBP is a novel tumour suppressor in solid tumours

Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.

2022-03-23 | PXD012098 | Pride

Specific endothelical cells govern nanoparticle entry into solid tumours

Project description:Specific endothelical cells govern nanoparticle entry into solid tumours

| PRJNA723561 | ENA

Gut microbiome-derived bacterial extracellular vesicles in patients with solid tumours

Project description:In this study, we performed a comparative analysis of gut microbiota composition and gut microbiome-derived bacterial extracellular vesicles (bEVs) isolated from patients with solid tumours and healthy controls. After isolating bEVs from the faeces of solid tumour patients and healthy controls, we performed spectrometry analysis of their proteomes and next-generation sequencing (NGS) of the 16S gene. We also investigated the gut microbiomes of faeces from patientsand controls using 16S rRNA sequencing. Machine learning was used to classify the samples into patients and controls based on their bEVs and faecal microbiomes.

2024-08-08 | PXD047510 | Pride

KP lung tumours

Project description:KP lung tumours

| PRJNA577056 | ENA

Paired tumour biopsy gene expression data from patients with solid tumours, before and after combination treatment.

Project description:Gene expression quantification of PanCancer IO genes from paired tumour biopsies from 24 patients with pan-cancer solid tumours, before and after treatment with MTL-CEBPA and pembrolizumab.

2024-10-23 | GSE233860 | GEO

Transcriptional Profiling of Mouse Tumours

Project description:Transcriptional Profiling of Mouse Tumours

| PRJNA905435 | ENA

Bladder Tumours O-Glycoproteomics

Project description:Bladder carcinogenesis and tumour progression is accompanied by profound alterations in protein glycosylation. These include the presence of short chain O-glycans such as Tn and T antigens and their sialylated counterparts sialyl-Tn(STn) and sialyl-T(ST). The presence of such structures is commonly associated with poor prognosis. In search for prognosis biomarkers and novel therapeutic targets we have screened, using immunohistochemistry, a series of bladder tumours with differing clinicopathology for these short-chain O-glycans. Aiming at identifying protein targets, we have studied the O-glycoproteome of a pool of STn positive tumours from muscle invasive bladder cancer (MIBC) patients.

2017-08-17 | PXD006813 | Pride

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