Biology subjects

Leroy, K.

Publications and source records attributed to Leroy, K..

3 recordsLinked to original sources

bioRxiv2025

Longitudinal cell-free DNA methylome and fragmentome profiles in health uncover signatures of cell type and demographic origin

Cell-free DNA (cfDNA) is a powerful analyte for liquid biopsy applications. However, the composition and fragmentation of cfDNA in health remains incompletely characterized. Here, we profiled 432 plasma cfDNA samples from healthy individuals using targeted enzymatic methyl-sequencing, allowing cell-type of origin inference and assessment of fragmentation features. Both in a diurnal and a cross-sectional cohort, we observed that cfDNA levels and cellular contributions show lower variability within than between individuals. Hematopoietic lineages are the dominant cfDNA sources, with interindividual variability particularly evident in granulocyte contributions. Demographic factors such as sex, age and body mass index (BMI) contribute to changes in the contribution of various blood cell types, and cfDNA concentrations are 1.6-fold higher in early morning collections (P = 1.8 x 10-5). By integrating cell-type-specific cfDNA methylation, fragment size and dinucleotide end motif information, we demonstrate distinct associations of these characteristics with specific cell types. Granulocyte-derived fragments showed a consistent enrichment in mononucleosomal sizes (P = 3.5 x 10-54) and CC end motifs, while also cfDNA from non-hematopoietic cells exhibited distinct size and end-motif profiles. In addition, we observed hypomethylated DNA to be associated with shorter fragment sizes and altered end-motif frequencies, emphasizing interactions between DNA methylation, nuclease activity and chromatin context in shaping cfDNA features. Together, our results provide a view on processes and cell types involved in cfDNA biogenesis in healthy individuals. They underscore that demographic variables and sampling time should be considered for cfDNA-based assay design, but also highlight novel opportunities to improve the representation of specific cell types in cfDNA, thus providing a foundation for optimizing cfDNA diagnostics by leveraging multiple axes of information.

genomics↗

bioRxiv2025

The Olfactory Epithelium: A Critical Gateway for Pathological Tau Propagation and a Target for Mitigating Tauopathy in the Central Nervous System

Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimers disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g. EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OEs middle stratum and in the OBs olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Complete stripping of the OE by intranasal administration of ZnSO4 led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human post-mortem samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to ageing or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.

neuroscience↗

bioRxiv2024

Differential predictive value of resident memory CD8+T cell subpopulations in non-small-cell lung cancer patients treated by immunotherapy

A high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. However, in preclinical models, only some subpopulations of TRM are associated with cancer vaccine efficacy. We identified two main TRM subpopulations in tumor-infiltrating lymphocytes derived from non-small cell lung cancer (NSCLC) patients: one co-expressing CD103 and CD49a (DP), and the other expressing only CD49a (MP); both exhibiting additional TRM surface markers like CD69. DP TRM exhibited greater functionality compared to MP TRM. Analysis of T-cell receptor (TCR) repertoire and of the stemness marker TCF-1 revealed shared TCRs between populations, with the MP subset appearing more progenitor-like phenotype. In two NSCLC patient cohorts, only DP TRM predicted PD-1 blockade response. Multivariate analysis, including various biomarkers (CD8, TCF1+CD8+T cells, and PD-L1) associated with responses to anti-PD(L)1, showed that only intra-tumoral infiltration by DP TRM remained significant. This study highlights the non-equivalence of TRM populations and emphasizes the importance of distinguishing between them to better define their role in antitumor immunity and as a biomarker of response to immunotherapy.

immunology↗