Biology subjects

Brunel, S.

Publications and source records attributed to Brunel, S..

5 recordsLinked to original sources

bioRxiv2025

Redirecting cytomegalovirus immunity against pancreas cancer for immunotherapy

Immunotherapy shows limited success in pancreatic cancer, largely due to a low mutational burden and immunosuppressive microenvironment. Here we hypothesized that pre-existing antiviral immunity can be redirected to control pancreatic tumors. Cytomegalovirus (CMV, a {beta}-herpesvirus) was chosen, as the majority of the population is infected and it induces an extremely large/broad memory T cell response. Mice latently infected with murine CMV (MCMV) were orthotopically implanted with pancreatic cancer cells and treated with systemic injections of MCMV T-cell epitopes. The therapy promoted preferential accumulation of MCMV-specific T cells within pancreatic tumors, delaying tumor growth and increasing survival. Immunophenotyping and scRNAseq analyses showed these T cells were highly activated and cytotoxic, leading to increased tumor necrosis and caspase-3 activation. Finally, therapy was enhanced when combined with subtherapeutic doses of gemcitabine chemotherapy. Together, these results show that CMV-specific T cells can be repurposed to combat pancreatic cancer. SignificanceOur studies reveal that CMV-specific viral memory T cells can be re-directed to control a solid tumor normally refractory to immunotherapy via a simple, intravenous injection of T cell peptide epitopes. This mutation agnostic approach has significant potential for the development of "off-the-shelf" therapeutics by stimulating pre-existing antiviral memory and it is widely applicable due to the high prevalence of CMV.

cancer biology↗

bioRxiv2024

A noncanonical glycoprotein H complex enhances cytomegalovirus entry

Human cytomegalovirus (HCMV) causes severe birth defects, lifelong health complications, and $4 billion in annual costs in the United States alone. A major challenge in vaccine design is the incomplete understanding of the diverse protein complexes the virus uses to infect cells. In Herpesviridae, the gH/gL glycoprotein heterodimer is expected to be a basal element of virion cell entry machinery. For HCMV, gH/gL forms a "trimer" with gO and a "pentamer" with UL128, UL130, and UL131A, with each complex binding distinct receptors to enter varied cell types. Here, we reveal a third glycoprotein complex, abundant in HCMV virions, which significantly enhances infection of endothelial cells. In this "3-mer" complex, gH, without gL, associates with UL116 and UL141, an immunoevasin previously known to function in an intracellular role. Cryo-EM reveals the virion-surface 3-mer is structurally unique among Herpesviridae gH complexes, with gH-only scaffolding, UL141-mediated dimerization and a heavily glycosylated UL116 cap. Given that antibodies directed at gH and UL141 each can restrict HCMV replication, our work highlights this virion surface complex as a new target for vaccines and antiviral therapies.

microbiology↗

bioRxiv2020

Strong effect of Penicillium roqueforti populations on volatile and metabolic compounds responsible for aromas, flavour and texture in blue cheeses

Studies of food microorganism domestication can provide important insight into adaptation mechanisms and lead to commercial applications. Penicillium roqueforti is a fungus with four genetically differentiated populations, two of which were independently domesticated for blue cheese-making, with the other two populations thriving in other environments. Most blue cheeses are made with strains from a single P. roqueforti population, whereas Roquefort cheeses are inoculated with strains from a second population. We made blue cheeses in accordance with the production specifications for Roquefort-type cheeses, inoculating each cheese with a single P. roqueforti strain, using a total of three strains from each of the four populations. We investigated differences between the cheeses made with the strains from the four P. roqueforti populations, in terms of the induced flora, the proportion of blue color, water activity and the identity and abundance of aqueous and organic metabolites as proxies for proteolysis and lipolysis as well as volatile compounds responsible for flavor and aroma. We found that the population-of-origin of the P. roqueforti strains used for inoculation had a minor impact on bacterial diversity and no effect on the abundance of the main microorganism. The cheeses produced with P. roqueforti strains from cheese populations had a higher percentage of blue area and a higher abundance of the volatile compounds typical of blue cheeses, such as methyl ketones and secondary alcohols. In particular, the Roquefort strains produced higher amounts of these aromatic compounds, partly due to more efficient proteolysis and lipolysis. The Roquefort strains also led to cheeses with a lower water availability, an important feature for preventing spoilage in blue cheeses, which is subject to controls for the sale of Roquefort cheese. The typical appearance and flavors of blue cheeses thus result from human selection on P. roqueforti, leading to the acquisition of specific features by the two cheese populations. These findings have important implications for our understanding of adaptation and domestication, and for cheese improvement.

evolutionary biology↗

bioRxiv2019

HVEM blockade initiates tumor cell death by innate immunity and improves anti-tumor response by human T cells in NSG immuno-compromised mice

BackgroundTNFRSF14 (herpes virus entry mediator (HVEM) delivers a negative signal to T cells through the B and T Lymphocyte Attenuator (BTLA) molecule and has been associated with a worse prognosis in numerous malignancies. A formal demonstration that the HVEM/BTLA axis can be targeted for cancer immunotherapy is however still lacking. MethodsWe used immunodeficient NOD.SCID.gc-null mice reconstituted with human PBMC and grafted with human tumor cell lines subcutaneously. Tumor growth was compared using linear and non linear regression statistical modeling. The phenotype of tumor-infiltrating leukocytes was determined by flow cytometry. Statistical testing between groups was performed by a non-parametric t test. Quantification of mRNA in the tumor was performed using NanoString pre-designed panels. Bioinformatics analyses were performed using Metascape, Gene Set Enrichment Analysis and Ingenuity Pathways Analysis with embedded statistical testing. ResultsWe showed that a murine monoclonal antibody to human HVEM significantly impacted the growth of various HVEM-positive cancer cell lines in humanized NSG mice. Using CRISPR/cas9 mediated deletion of HVEM, we showed that HVEM expression by the tumor was necessary and sufficient to observe the therapeutic effect. Tumor cell killing by the mAb was dependent on innate immune cells still present in NSG mice, as indicated by in vivo and in vitro assays. Mechanistically, tumor control by human T cells by the mAb was dependent on CD8 T cells and was associated with an increase in the proliferation and number of tumor-infiltrating leukocytes. Accordingly, the expression of genes belonging to T cell activation pathways, such as JAK/STAT and NFKB were enriched in anti-HVEM-treated mice, whereas genes associated with immuno-suppressive pathways were decreased. Finally, we developed a simple in vivo assay to directly demonstrate that HVEM/BTLA is an immune checkpoint for T-cell mediated tumor control. ConclusionsOur results show that targeting HVEM is a promising strategy for cancer immunotherapy.

immunology↗

bioRxiv2017

Decoding the regulatory logic of the Drosophila male stem cell system

In the past decade, the importance of the niche to provide regulatory inputs to balance stem cell self-renewal and differentiation has become clear. However, the regulatory interplay between stem cells and their niche at the whole genome level is still poorly understood. To elucidate the mechanisms controlling stem cells and their progenies as they progress through their developmental program at the transcriptional level, we recorded the regulatory program of two independent cell lineages in the Drosophila testis stem cell model. To this end, we identified genes active in the soma or germline as well as genome-wide binding profiles of two essential transcription factors, Zfh-1 and Abd-A, expressed in somatic support cells and crucial for fate acquisition of both cell lineages. Our data identified key roles for TOR signalling, signal processing V-ATPase proton pumps and the nuclear transport engaged nucleoporins and we demonstrate their importance in controlling germline maintenance, proliferation and differentiation from the support side. To make our dataset publicly available and support quick and intuitive data mining, we generated an interactive online analysis tool. Applying our tool for comparative analysis, we uncovered conserved core gene sets of adult stem cells across species boundaries. We have tested the functional relevance of these genes in the Drosophila testis and intestine and find a striking overrepresentation of stem cell defects when the corresponding genes were depleted. In summary, our dataset and interactive platform represents a versatile tool for identifying novel gene networks active in diverse stem cell types and provides a valuable resource for elucidating the multifaceted regulatory inputs required to guide proper stem cell behaviour.

developmental biology↗