Biology subjects

Charrot, S.

Publications and source records attributed to Charrot, S..

3 recordsLinked to original sources

bioRxiv2025

Single-cell mass cytometry maps the evolution of immune cell signatures predictive of acute graft-versus-host disease

Allogeneic haematopoietic stem-cell transplantation (AHST) can cure patients with many diseases, but harmful acute graft-versus-host disease (aGvHD) remains a challenge. Many immune cells are implicated in the pathogenesis and control of alloreactive T-cell responses causing aGvHD, but the functionally dominant cells at different times remain unknown. Using mass cytometry to simultaneously assess alloreactive and immunoregulatory cell populations after AHST, we identified a robust early immune signature predictive of aGvHD rich in CD4 effector memory T-cells and deficient in functionally allosuppressive NK cells. Additionally, network analysis identified a heterogeneous immunoregulatory cell group (IRCG) that more accurately predicted aGVHD than any individual cell populations or established serum biomarkers. Immune signatures preceding aGvHD evolved over time, with qualitative and quantitative changes in both the alloreactive T-cell compartment and the constituent components of the IRCG. In mapping how alloreactive and immunoregulatory cell populations evolve temporally, we provide mechanistic insight into dynamic control of alloreactivity supporting development of time-sensitive targeted strategies to reduce aGvHD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/640331v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@12bb519org.highwire.dtl.DTLVardef@7e9dbcorg.highwire.dtl.DTLVardef@a5b041org.highwire.dtl.DTLVardef@1d69a82_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

LIMD1 Loss as an Early Driver of PD-L1 Upregulation and Immune Evasion in Lung Cancer

LIMD1 is a tumour suppressor gene frequently lost in non-small cell lung cancer (NSCLC), but its role in cancer-immune cell interactions remains unexplored. Here, we demonstrate that LIMD1 loss results in upregulation of the key immune checkpoint protein PD-L1. Using multi-region sequencing from the TRACERx dataset, we identify that LIMD1 loss is clonal in over 80% of squamous cell carcinoma (LUSC) and 40% of lung adenocarcinoma (LUAD) cases, correlating with increased PD-L1 expression. LIMD1 deficiency results in upregulation of basal and IFN{gamma}-induced PD-L1 expression in NSCLC cells and, consistent with its early loss during oncogenesis, in primary human small airway epithelial cells. Mechanistically, we demonstrate that LIMD1 interacts with the E3 ubiquitin ligase ARIH1 to mediate efficient PD-L1 ubiquitination and degradation, a process that is significantly impaired in LIMD1-deficient cells, resulting in increased PD-L1 stability. As a consequence, LIMD1-deficient tumour cells suppressed CD8+ T cell activation in vitro, and blockade of PD-L1 reversed this suppression. Clinically, we show that LIMD1 loss is associated with enhanced response to immune checkpoint inhibitors (ICIs) in NSCLC patient cohorts, revealing a novel cancer cell-intrinsic correlation of ICI efficacy. Our results uncover a tumour suppressor-mediated mechanism of PD-L1 expression and pave the way for stratified immunotherapy approaches in LIMD1-/- NSCLC.

cancer biology↗

bioRxiv2022

Low HER2 enables dedifferentiation and transformation of normal breast epithelial cells via chromatin opening

Overexpression of the human epidermal growth factor 2 (HER2) protein in breast cancer patients is a predictor of poor prognosis and resistance to therapies. Despite significant advances in the development of targeted therapies and improvements in the 5-year survival rate of metastatic HER2-positive breast cancer patients, a better understanding of the disease at an early stage is needed to prevent its progression. Here, we used an inducible breast cancer transformation system that allows investigation of early molecular changes at high temporal resolution. HER2 overexpression to similar levels as those observed in a subtype of HER2 positive breast cancer patients induced transformation of MCF10A cells and resulted in gross morphological changes, increased anchorage-independent growth of cells, and altered transcriptional programme of genes associated with oncogenic transformation. Global phosphoproteomic analysis during the first few hours of HER2 induction predominantly detected an increase in protein phosphorylation. Intriguingly, this correlated with a wave of chromatin opening, as measured by ATAC-seq on acini isolated from 3D cell culture. We observed that HER2 overexpression leads to reprogramming of many distal regulatory regions and promotes reprogramming-associated heterogeneity. We found that a subset of cells acquired a dedifferentiated breast stem-like phenotype, making them likely candidates for malignant transformation. Our data show that this population of cells, which counterintuitively enriches for relatively low HER2 protein abundance and increased chromatin accessibility, possesses transformational drive, resulting in increased anchorage-independent growth in vitro compared to cells not displaying a stem-like phenotype. Our data provide a discovery platform for signalling to chromatin pathways in HER2-driven cancers, offering an opportunity for biomarker discovery and identification of novel drug targets.

cancer biology↗