Biology subjects

Fabre, T.

Publications and source records attributed to Fabre, T..

4 recordsLinked to original sources

bioRxiv2025

Myeloid cells contribute to bystander CD8 T cell accumulation in metabolic-associated steatohepatitis and are sufficient for fibrosis

Background & AimsMetabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver fibrosis, morbidity, and mortality. It is characterized by the accumulation of fat in hepatocytes causing cell death followed by stromal cell activation and scar deposition at later disease stages. While a marked accumulation of cytotoxic CD8 T cells is observed in MASH in humans and mice, the role of adaptive immune cells in fibrosis progression remains debated. MethodsTranscriptional data were curated from human datasets and preclinical mouse models, including mice deficient in TCR{beta} T cells (Tcrb-/-), which lack conventional CD4 helper and CD8 cytotoxic T cells, in diet-induced fibrosing MASH for single-cell RNA-sequencing. Specific human and mouse liver transcriptomic immune signatures were corroborated by flow cytometry and immunofluorescence. ResultsxMASH was associated with the expansion of lymphocytes and myeloid cells. Auto-aggressive CXCR6+PD1+FASLG+ CD8 T cells were enriched in livers of high-fat-diet-fed mice and correlated with MASH and fibrosis. Notably, Tcrb-deficient mice in a chemical and dietary preclinical MASH model developed fibrosis to the same extent as wild-type mice and exhibited exacerbated pro-fibrotic type 3 inflammation. Loss of conventional CD8 T cells neither impacted myeloid cell number nor phenotype within the fibrotic niche. Neutrophil- and non-conventional lymphocyte-derived GM-CSF and IL-17A were central drivers in the fibrotic niche composed of pathogenic macrophages and activated myofibroblasts. Furthermore, myeloid cells were identified as the main source of CXCL16 in diseased livers, retaining auto-aggressive CD8 T cells to the scar and contributing to their accumulation. Thus, non-adaptive cells, including scar-associated macrophages (SAMs) and myofibroblasts, are sufficient for MASH-driven fibrosis in this model. ConclusionsTargeting myeloid cells and fibroblasts should be prioritized as anti-fibrotic therapies for MASH. Graphical abstractThe immunopathological niche in fibrosis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/694415v3_ufig1.gif" ALT="Figure 1000"> View larger version (47K): org.highwire.dtl.DTLVardef@122a24org.highwire.dtl.DTLVardef@8ca28borg.highwire.dtl.DTLVardef@103907borg.highwire.dtl.DTLVardef@10280e3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsAdaptive and innate immune cells localize to the human MASH fibrotic niche CD8 T cells increase with MASH severity while MHC-II+ cells accumulate with fibrosis CXCR6+FASLG+ CD8 auto-aggressive T cells accumulate at the scar CXCL16+ scar-associated macrophages retain CD8 T cells in the fibrotic MASH niche Liver injury, inflammation and fibrosis persist in the absence of conventional T cells Impact and implicationsMetabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease in which fibrosis is a key determinant of patient outcomes and survival. This study demonstrates that fibrosis in MASH can develop independent of conventional T cell immunity, driven by myeloid cells including scar-associated macrophages (SAMs) and neutrophils within a localized hepatic niche in mice and humans. This highlights the need to prioritize innate immune mechanisms as key drivers of chronic (late-stage) liver disease for researchers and clinicians developing anti-fibrotic therapies.

immunology↗

bioRxiv2025

Therapeutic Blockade of Type 2 Cytokines and PD1 Unleashes Anti-Tumor Immunity Through Coordinated Reprogramming of Innate and Adaptive Immune Surveillance

BackgroundCheckpoint inhibitors improve survival in patients with several types of tumors. However, resistance to checkpoint inhibitors creates an opportunity for patients to benefit from novel immunotherapies. The type 2 cytokines IL-4, IL-13 and TSLP have been implicated in suppressing anti-tumor immune responses through T and myeloid cells. Our current study tested whether combined therapeutic blockade of IL-4, IL-13 and TSLP improved anti-tumor immunity alone and in combination with PD1 antagonism. MethodsWe used in vitro experiments with primary cells to identify cell types likely to participate in controlling tumors upon IL-4, IL-13, TSLP and PD1 blockade. Therapeutic blockade in the subcutaneous CT26 model tested in vivo tumor growth inhibition and associated immunological changes. Bioinformatic analysis of human tumor bulk RNA sequencing data probed for survival associations with IL-4/IL-13 and TSLP transcriptional responses. ResultsIn vitro, IL-4 suppressed T cell-mediated tumor growth inhibition and reduced monocyte-derived dendritic cell expression of proteins associated with anti-tumor immunity. In vivo, blocking IL-4, IL-13, TSLP and PD1 improved tumor growth inhibition by creating "hotter" tumors. This was associated with repolarization of CD4 and CD8 T cells and shifts in monocyte, conventional type 1 and type 2 (or monocyte-derived) dendritic cell programs. Transcriptional responses to IL-4/IL-13 and TSLP were associated with poor survival outcomes across patients with several types of cancers. ConclusionTherapeutic blockade of IL-4, IL-13 and TSLP may drive immunological tumor growth inhibition in subsets of cancer patients alone and in combination with checkpoint inhibitors. Improved tumor growth inhibition was likely driven through augmented cytotoxic T cell priming in secondary lymphoid organs and improved reactivation by repolarized monocytes and dendritic cells in tumors.

cancer biology↗

bioRxiv2023

Stricturing Crohn's disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions

BackgroundFibroblasts play a key role in stricture formation in Crohns disease (CD) but understanding its pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. MethodsWe performed scRNAseq of 13 fresh full thickness CD resections containing non-involved, inflamed non-strictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 99 tissue samples and 409,001 cells. We validated cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next generation sequencing, proteomics and animal models. ResultsOur integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture-selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and upregulated, and its pro-fibrotic function was validated by NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and two animal models of experimental colitis. ConclusionA full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and opens potential therapeutic developments.

immunology↗

bioRxiv2022

Identification of a Broadly Fibrogenic Macrophage Subset Induced by Type 3 Inflammation in Human and Murine Liver and Lung Fibrosis

Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in the progression and resolution of fibrosis. Identifying the unique fibrogenic macrophages that are found in human fibrotic tissues could lead to new and more effective treatments for fibrosis. Here we used human liver and lung single cell RNA sequencing datasets to identify a unique subset of CD9+ TREM2+ macrophages expressing SPP1, GPNMB, FABP5, and CD63 with strong pro-fibrotic activity. This population was validated across orthogonal techniques, species and tissues. These macrophages were enriched at the outside edges of scarring adjacent to activated mesenchymal cells, and in the fibrotic niche across species and organs. Neutrophils producing the type 3 cytokines GM-CSF and IL-17A, and expressing MMP9, which participates in the activation of TGF-{beta}1, clustered with these scar-associated macrophages. Using in vitro primary human cell assays, we determined that GM-CSF, IL-17A and TGF-{beta}1 drive the differentiation of these scar-associated macrophages, and that co-culture of monocyte-derived macrophages with hepatic stellate cells and TGF-{beta}1 augmented type 1 collagen deposition. In vivo blockade of GM-CSF, IL-17A or TGF-{beta}1 with small or large molecules reduced scar-associated macrophage expansion and fibrosis in multiple models of hepatic and pulmonary fibrosis. Our work demonstrates that a specific scar-associated macrophage population is linked with fibrosis across species and tissues. It further provides a strategy for unbiased discovery, triage and preclinical validation of therapeutic targets within this fibrogenic macrophage population.

immunology↗