Biology subjects

Pecqueur, C.

Publications and source records attributed to Pecqueur, C..

6 recordsLinked to original sources

bioRxiv2026

Functional diversity of Vγ9Vδ2 T cells overcomes glioblastoma state plasticity and antigen heterogeneity

Glioblastoma (GBM) is characterized by a high degree of cellular plasticity and intra-tumoral heterogeneity, which frequently leads to the failure of standard therapies, including immunotherapies. While chimeric antigen receptor (CAR) T cells offer a potent means of MHC-independent tumor recognition, their efficacy is hampered by the coexistence of distinct molecular states, gathered as proneural (PN) and mesenchymal (MES) phenotypes. Here, we demonstrate that gangliosides GD2 and O-acetylated GD2 (OAcGD2) are preferentially expressed by PN cells whereas MES cells display reduced expression due to upregulated ganglioside catabolism. Conversely, MES cells are known to exhibit high expression of stress-induced ligands recognized by V{gamma}9V{delta}2 T cells. We show that while engineering V{delta}2T cells with GD2- or OAcGD2-specific CAR enables the elimination of PN cells, it also facilitates the immune escape of MES cells in heterogeneous 3D-tumoroid models. Mechanistically, we reveal a hierarchy of receptor engagement, where CAR signaling predominates leading to the structural and functional exclusion of endogenous TCR from the immunological synapse. To address this receptor competition, we propose a strategy that leverages the functional effector diversity by combining untransduced and CAR-engineered V{delta}2T cells. This dual approach provides a dynamic safety net by ensuring the simultaneous elimination of PN and MES cells and preventing the selective outgrowth of resistant cells. Our findings establish a conceptual framework for designing off-the-shelf immunotherapies tailored to the metabolic and phenotypic plasticity of resistant solid tumors.

cancer biology↗

bioRxiv2026

Chronopharmacological targeting of mitochondrial dihydroorotate dehydrogenase prevents diet-induced obesity in male mice

Daily hepatic mitochondrial rhythms are strengthened by time-restricted feeding in diet-induced obesity in male mice, as shown by metabolomics, including an early enhancement of oscillations within the de novo pyrimidine pathway. We tested whether timed inhibition of dihydroorotate dehydrogenase (DHODH, which links pyrimidine synthesis to respiratory-chain flux), can reproduce selected TRF-associated mitochondrial and metabolic effects. Administering the short-half-life inhibitor BAY2402234 at dawn transiently decreased DHODH activity, restored daily mitochondrial oxidative dynamics (ubiquinone/ubiquinol ratio), and amplified rhythms of respiratory exchange ratio and mitochondrial dynamics-related markers upon high-fat diet. Under ZT0 dosing, mice showed reduced weight gain, reduced adiposity and hepatic triglycerides, and improved glucose tolerance without changes in food intake; while ZT12 dosing was ineffective. Hepatic Dhodh knockdown did not reproduce the anti-obesity phenotype, and uridine supplementation blunted BAY2402234 benefits, implicating de novo pyrimidine flux. Our findings reveal rhythm-aware DHODH inhibition as a chronopharmacological preclinical candidate approach against overnutrition.

physiology↗

bioRxiv2025

Inhibiting EZH2 Alleviates Osteoarthritis and Pain in an Experimental Murine Model Through Modulating Synovial and Macrophage Inflammation, Axon Guidance, and Osteoclastogenesis

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for H3K27 trimethylation, has emerged as a potential therapeutic target in osteoarthritis (OA). However, its contribution to the multicellular mechanisms driving joint degeneration and pain remains poorly understood. Here, we investigated the effects of pharmacological EZH2 inhibition in a pain-relevant murine OA model and explored its cellular and molecular consequences across OA-associated cell populations. OA was induced in mice by intra-articular monosodium iodoacetate (MIA) injection followed by local administration of the EZH2 inhibitor EPZ-6438. Joint pathology and pain-related behaviors were assessed by histological and functional analyses. Mechanistic studies were performed in primary human OA fibroblast-like synoviocytes and bone marrow-derived cells using targeted gene expression analyses, proteomics and ChIP-seq approaches. EZH2 inhibition reduced cartilage damage, synovial inflammation and pain-related behavioral alterations in vivo. In OA synoviocytes, EPZ-6438 decreased the expression of inflammatory, catabolic and pain-associated mediators while promoting autophagy-related responses. Proteomic and ChIP-seq analyses revealed EZH2-dependent regulation of inflammatory pathways, cellular homeostasis and neuronal-associated processes, including axon guidance-related pathways. ChIP-seq further identified inflammation-dependent EZH2 recruitment to promoters of neurodevelopmental regulators, including PAX6, suggesting a potential contribution of EZH2 to neuronal-associated mechanisms in OA. In addition, EZH2 inhibition reduced macrophage inflammatory activation and osteoclast differentiation. Together, these findings identify EZH2 as a candidate epigenetic regulator linking inflammatory, neuroimmune and osteoimmune pathways across the osteoarthritic joint. Targeting EZH2 may represent a therapeutic strategy to simultaneously modulate joint inflammation, remodeling and pain-associated pathways.

physiology↗

bioRxiv2023

Targeting pediatric High-Grade Gliomas with OAcGD2-CAR Vδ2 T cells

PurposePediatric high-grade gliomas (pHGG) belong to a family of rare childrens cancers which are treated with radiotherapy, based on adult high-grade glioma standard of care. However, new treatments are definitively required since actual ones are unable to extend survival by more than a few months in most patients. In this study, we investigate a Chimeric Antigen Receptor (CAR)-T cell immunotherapy targeting the OAcGD2 ganglioside, using either conventional {beta} or V{delta}2 T cells as effectors. Materials and methodsUsing relevant human primary models of pHGG, we first characterized the innate V{delta}2 T cell immunoreactivity. Then, following the validation of OAcGD2 expression in these tumor cells, we evaluated both {beta} and V{delta}2 OAcGD2-CAR-T cell immunoreactivity using various methods including videomicroscopy, FACS and cytotoxicity assays. ResultsWe showed that pHGG primary cells are not spontaneously recognized and killed by V{delta}2 T cells but significantly expressed the OAcGD2 ganglioside. Accordingly, both {beta} and V{delta}2 T cells engineered to express a CAR against the OAcGD2 efficiently killed pHGG cells in 2D and 3D models. Importantly, only V{delta}2 T cells transduced with the complete OAcGD2-CAR eliminated pHGG cells, in contrast to conventional {beta} CAR-T cells that killed tumor cells even in the absence of CAR expression, highlighting the allogeneic potential of V{delta}2 CAR-T cells. ConclusionOur study demonstrates the preclinical relevance of targeting OAcGD2 in pHGG using CAR-T cells. Furthermore, we also clearly demonstrate the clinical benefits of using V{delta}2 T cells as CAR effectors in allogeneic settings allowing an off-the-shelf immunotherapy.

cancer biology↗

bioRxiv2022

Pyruvate carboxylation identifies Glioblastoma Stem-like Cells opening new metabolic strategy to prevent tumor recurrence

Glioblastoma (GBM) are currently associated with a dismal prognosis due to therapeutic resistance. Within the diverse tumor subpopulations, Glioblastoma Stem-like Cells (GSC) have been involved in GBM recurrence. In our study, we demonstrated that these tumor cells can be identified through singular mitochondrial alternative metabolisms. Combining state-of-the-art metabolic studies and the development of a straightforward tumoroid model recapitulating key features of primary GBM cultures, we uncovered a significant use of -ketoglutarate reductive carboxylation and pyruvate carboxylation in tumoroid GBM cells, catalyzed respectively by isocitrate dehydrogenase and pyruvate carboxylase enzymes. We demonstrated that these singular metabolic features are shared by GBM cells from the mesenchymal subtype and radiation-escaping cells, also involved in recurrence. Finally, we demonstrated that pyruvate carboxylation is required for GBM cell survival in hypoxic niches where glutamine is restricted. Thus, besides providing a new way to identify GSC, our study also opens new therapeutic strategy to limit GBM recurrence.

cancer biology↗

bioRxiv2021

Mechanistic insights of radiation-induced endothelial senescence impelling glioblastoma genomic instability at relapse

Despite aggressive clinical protocol, all glioblastoma (GBM) recur at the initial site within the irradiated peritumoral microenvironment. Whereas irradiated microenvironment has been recently proposed to accelerate GBM relapse, molecular and cellular mechanisms remain unknown. Here, using relevant in vitro and in vivo models, we decipher how radiation-induced endothelial senescence drives the emergence of aggressive GBM cells. Secretome (SASP) of radiation-induced senescent (RIS) endothelium enhances genomic instability and intratumoral heterogeneity in irradiated GBM cells. In-depth molecular studies revealed that CXCL5 and CXCL8, from the SASP, activate CXCR2 receptor on tumor cells leading to increased DNA hyper-replication, micronuclei formation and aneuploidy. Importantly, through CXCL5/8-CXCR2 axis activation, this SASP increases GBM aggressiveness in vivo. Both chemokines were detected in relapsing, but not primary, GBM biopsies and positively correlated with worst patient outcome. In conclusion, we identify new molecular and preclinical insights of relapsing GBM aggressiveness where RIS vascular niches fuel aggressive tumor emergence.

cancer biology↗