Biology subjects

Fonteneau, J.-F.

Publications and source records attributed to Fonteneau, J.-F..

4 recordsLinked to original sources

bioRxiv2026

A novel tumor-targeted interferon-α/-β receptor 1 antagonist increases replication of oncolytic vesicular stomatitis virus in a mouse mesothelioma model

Type I Interferons (IFN-I) are cytokines with pleiotropic activities involved in antiviral and antitumor immune responses. They can reduce oncolytic virus replication in tumor cells by inducing expression of interferon stimulated genes (ISG) with antiviral functions. To specifically neutralize the IFN-/-{beta} receptor (IFNAR) on specific cell types, we created novel IFNAR1-targeted antagonists constituted of a high-affinity nanobody targeting a specific cell surface marker conjugated to a low-affinity blocking nanobody targeting IFNAR1. We first show in vitro and in vivo that such an antagonist targeting the mouse CD20 molecule (mCD20) inhibits IFNAR signaling only in B cells among splenocytes. We then showed in vitro that a human CD20 (hCD20)-targeted antagonist blocks IFNAR signaling and induces vesicular stomatitis virus (VSV) oncolytic activity against IFN-11-treated AK7 mesothelioma or B16 melanoma cells only if these cells express hCD20. In vivo, we show that the antagonist binds to hCD20 and enhances VSV replication by inhibiting ISG expression specifically in hCD20+ AK7 mesothelioma tumors. Altogether our results demonstrate the efficient and cell-type specific inhibition of IFNAR signaling through the use of these novel IFNAR1 antagonists, both in vitro and in vivo. These antagonists could have many therapeutic applications given the importance of IFN-I in numerous diseases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/729496v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@4e76b6org.highwire.dtl.DTLVardef@153c39borg.highwire.dtl.DTLVardef@4f0948org.highwire.dtl.DTLVardef@ea8d85_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC synopsisIn this study, we created cell-specific IFNAR antagonists that allow to inhibit selectively IFNAR signaling in particular types of cell. We show that this antagonist can be used to target IFNAR at the surface of tumor cells that lead to the inhibition of IFNAR signaling and ISG expression in these cells rendering them more permissive to VSV replication. Beside antitumor virotherapy, these novel antagonist could be useful to study role of IFN-I in normal or pathological context.

immunology↗

bioRxiv2026

Oncolytic measles virus reprograms the tumor microenvironment in a vascularized mesothelioma-on-chip model

Pleural mesothelioma (PM) is a rare, aggressive cancer primarily caused by asbestos exposure and remains resistant to conventional chemotherapy. Although dual immune checkpoint inhibition (anti-PD-1/anti-CTLA-4) is now approved as first-line therapy, clinical benefit is limited to a small subset of patients, necessitating the need for alternative strategies. Oncolytic viruses (OVs) represent a promising approach as they selectively infect and lyse tumor cells while reprogramming the immunosuppressive tumor microenvironment (TME) into an immunostimulatory state. In PM, we previously showed that the attenuated Schwarz strain of measles virus (MV) oncolytic activity is mainly dependent on alterations in the type I interferon (IFN-I) pathway, rendering tumor cells sensitive to infection. Recently, we showed that monocytes/macrophages exposed to MV produce IFN-I, which protects PM cells via paracrine IFNAR signaling. This underscores the necessity of modeling the TME to accurately evaluate OV efficacy. Conventional rodent models are non-permissive to MV, and availability of fresh human PM tissue is scarce. We therefore developed a humanized 3D "vascularized mesothelioma-on-chip" (VMOC) model using microfluidic chips. It comprises two perfusable endothelial-lined parental vessels flanking a central secondary microvascular network (MVN), generated using human umbilical vein endothelial cells (HUVECs) embedded in fibrin and co-cultured alongside PM cells and primary human lung fibroblasts (hLFs). We characterized the integrity and functionality of the endothelial compartment as well as the cellular heterogeneity in VMOC using single-cell RNA sequencing. After administration of MV via the endothelial network, we observed infection and death of PM cells in addition to a strong activation of the type I interferon pathway and production of multiple inflammatory mediators. The VMOC model enables in vitro study of both MV infection and TME reprogramming, paving the way for a better understanding of the role of the TME in the response to treatment and for supporting the development of more personalized, targeted therapies for PM.

cancer biology↗

bioRxiv2025

A modified oncolytic measles virus exhibits strong immunotherapeutic potential through RIG-I activation by defective viral genomes

Oncolytic viruses can destroy tumors directly or by activating antitumor immunity, but balancing safety with potent immune stimulation remains challenging. Here, we show that deletion of the measles virus C protein, a key viral antagonist of innate immunity, reprograms the live-attenuated vaccine strain into a RIG-I-driven cancer immunotherapy. The resulting virus, MVdeltaC, accumulates defective viral genomes that activate RIG-I/MAVS signaling and trigger robust type I interferon and pro-inflammatory cytokine responses. MVdeltaC kills tumor cells more rapidly and efficiently than the parental virus and induces hallmarks of immunogenic cell death, including HMGB1 release and dendritic cell maturation. Intratumoral administration in immunocompetent mice bearing syngeneic neuroblastoma induced complete tumor regression in 90% of animals and established long-term antitumor memory. Antitumor responses were dependent on CD8 T and NK cells and were further enhanced by anti-CTLA-4 therapy or CD4 T-cell depletion. Prior measles immunization accelerated tumor clearance, indicating vaccine-boosted responses. MVdeltaC also controlled the growth of human mesothelioma, melanoma, and triple-negative breast cancer xenografts and patient-derived tumors in immunodeficient models. These findings establish MVdeltaC as a clinically ready, broad-spectrum immunotherapeutic that links RIG-I activation through defective viral genome generation to elicit potent and durable antitumor immunity. IMPACT StatementA modified measles virus lacking a viral innate immunity antagonist triggers potent antitumor responses via RIG-I sensing of defective viral genomes, revealing a new strategy for cancer immunotherapy.

immunology↗

bioRxiv2022

Heterogeneity of RNA editing in mesothelioma and how RNA editing enzyme ADAR2 affects mesothelioma cell growth, response to chemotherapy and tumor microenvironment

We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. Tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.

cancer biology↗