Biology subjects

Fournie, J.-J.

Publications and source records attributed to Fournie, J.-J..

5 recordsLinked to original sources

bioRxiv2023

IL-27 maintains cytotoxic Ly6C+ gamma delta T cells that arise from immature precursors

In mice, {gamma}{delta} T cells that express the co-stimulatory molecule, CD27, are committed to the IFN{gamma}-producing lineage in the thymus, and in the periphery, these cells play a critical role in host defence and anti-tumor immunity. Unlike {beta} T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted {gamma}{delta} T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFN{gamma}-producing {gamma}{delta} T cells. We found that immature CD27+Ly6C-- cells convert into mature CD27+Ly6C+ cells, and these mature cells control cancer progression while the immature cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature {gamma}{delta} T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human V{delta}2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C-- cells and human V{delta}1+ cells. These data reveal increased complexity within IFN{gamma}-producing {gamma}{delta} T cells, comprising of immature and terminally differentiated subsets, that offer new insights into unconventional T cell biology.

immunology↗

bioRxiv2020

A Boolean Model of the Formation of Tumour Associated Macrophages in an in-vitro Model of Chronic Lymphocytic Leukaemia

The tumour microenvironment is the collection of cells in and surrounding cancer cells in a tumour including a variety of immune cells, especially neutrophils and monocyte-derived macrophages. In a tumour setting, macrophages encompass a spectrum between a tumour-suppressive (M1) or tumour-promoting (M2) state. The biology of macrophages found in tumours (Tumour Associated Macrophages) remains unclear, but understanding their impact on tumour progression is highly important. In this paper, we perform a comprehensive analysis of a macrophage polarization network, following two lines of enquiry: (i) we reconstruct the macrophage polarization network based on literature, extending it to include important stimuli in a tumour setting, and (ii) we build a dynamical model able to reproduce macrophage polarization in the presence of different stimuli, including the contact with cancer cells. Our simulations recapitulate the documented macrophage phenotypes and their dependencies on specific receptors and transcription factors, while also elucidating the formation of a special type of tumour associated macrophages in an in-vitro model of chronic lymphocytic leukaemia. This model constitutes the first step towards elucidating the cross-talk between immune and cancer cells inside tumours, with the ultimate goal of identifying new therapeutic targets that could control the formation of tumour associated macrophages in patients.

systems biology↗

bioRxiv2020

Ly6C defines a subset of memory-like CD27+ γδ T cells with inducible cancer-killing function

In mice, IFN{gamma}-producing {gamma}{delta} T cells that express the co-stimulatory molecule, CD27, play a critical role in host defence and anti-tumour immunity. However, their phenotypic diversity, composition in peripheral and secondary lymphoid organs, similarity to {beta} T cells as well as homology with human {gamma}{delta} T cells is poorly understood. Here, using single cell RNA sequencing, we show that CD27+ {gamma}{delta} T cells consist of two major clusters, which are distinguished by expression of Ly6C. We demonstrate that CD27+Ly6C-- {gamma}{delta} T cells exhibit a naive T cell-like phenotype, whereas CD27+Ly6C+ {gamma}{delta} T cells display a memory-like phenotype, produce several NK cell-related and cytotoxic molecules and are highly similar to both mouse CD8+ T cells and mature human {gamma}{delta} T cells. In a breast cancer mouse model, depletion of CD27+ {gamma}{delta} T cells failed to affect tumour growth, but these cells could be coerced into killing cancer cells after expansion ex vivo. These results identify novel subsets of {gamma}{delta} T cells in mice that are comparable to human {gamma}{delta} T cells, opening new opportunities for {gamma}{delta} T cell-based cancer immunotherapy research.

immunology↗

bioRxiv2020

Mitochondrial determinants of response and resistance to venetoclax plus cytarabine duplet therapy in acute myeloid leukemia

The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen.

cancer biology↗

bioRxiv2019

Single-Cell Virtual Cytometer allows user-friendly and versatile analysis and visualization of multimodal single cell RNAseq datasets

The development of single cell transcriptomic technologies yields large datasets comprising multimodal informations such as transcriptomes and immunophenotypes. Currently however, there is no software to easily and simultaneously analyze both types of data. Here, we introduce Single-Cell Virtual Cytometer, an open-source software for flow cytometry-like visualization and exploration of multi-omics single cell datasets. Using an original CITE-seq dataset of PBMC from an healthy donor, we illustrate its use for the integrated analysis of transcriptomes and phenotypes of functional maturation in peripheral T lymphocytes from healthy donors. So this free and open-source algorithm constitutes a unique resource for biologists seeking for a user-friendly analytic tool for multimodal single cell datasets.

bioinformatics↗