Biology subjects

Touat, M.

Publications and source records attributed to Touat, M..

6 recordsLinked to original sources

bioRxiv2026

RIG-I RNA agonist activates immunostimulatory macrophages to enhance checkpoint immunotherapy for glioblastoma

Glioblastoma (GBM), the most frequent and aggressive primary brain tumor, remains refractory to all current therapies including surgical resection, chemotherapy, radiotherapy and immunotherapy. Immunosuppressive mechanisms in the GBM tumor microenvironment contribute to the lack of anti-tumor adaptive immunity. We found that a subset of tumor associated macrophages (TAMs) can be repolarized into an anti-tumor phenotype via agonist stimulation of the retinoic acid-inducible gene I (RIGI), a cytosolic double-stranded RNA pattern recognition receptor (PRR). In silico analysis of adult GBM datasets available in the public domain revealed that RIGI expression by a subset of activated TAMs positively correlated with patient survival. Studies in syngeneic mouse models of GBM showed that intratumoral delivery of stem-loop RNA 14 (SLR14), a RIG-I agonist, improved the efficacy of chemotherapy, radiotherapy and immunotherapy treatments, beyond the effects of other nuclei acid sensor agonists. We found that RIGI+ macrophages are the main drivers of SLR14 effect, combining activation of TAMs and priming of functional cytotoxic CD8+ T lymphocytes and NK cells. The anti-GBM effect of SLR14 is opening a significant new avenue for adult GBM treatment.

cancer biology↗

bioRxiv2024

A diverse landscape of FGFR alterations and co-mutations defines novel therapeutic strategies in pediatric low-grade gliomas

Alterations in Fibroblast growth factor receptor (FGFR)-family proteins frequently occur as oncogenes in many cancers, including a subset of pediatric gliomas. Here, we performed a genomic analysis of 11,635 gliomas across ages and found that 4.5% of all gliomas harbor FGFR alterations including structural variants (SV) and single nucleotide variants (SNV), with an incidence of almost 10% in pediatric gliomas. FGFR family members are differentially enriched by age, tumor grade, and histological subtype, with FGFR1-alterations associated with glioneuronal histologies and pediatric low-grade gliomas. Across development, we find FGFR1 expression in both neuronal and glial precursors, while FGFR3 expression is largely restricted to astrocytic lineages. Leveraging novel isogenic model systems, we confirm FGFR1 alterations to be sufficient to activate MAPK and mTOR signaling, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway inhibitors, including pan-FGFR inhibitors. Models driven by FGFR1 SVs exhibited different patterns of sensitivity compared to those driven by SNVs. Finally, we performed a retrospective analysis of clinical responses in children diagnosed with FGFR-driven gliomas and found that targeted MAPK or FGFR-inhibition with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome.

cancer biology↗

bioRxiv2024

The oncometabolite D-2-hydroxyglutarate promotes DNA hypermethylation at lineage-specific enhancers controlling microglial activation in IDHmut gliomas

Tumor-associated microglia and macrophages (TAMs), the most abundant myeloid populations in gliomas, shape immune responses through transcriptional programs influenced by the tumor microenvironment. Although these programs differ according to tumor IDH status, the underlying epigenetic mechanisms remain poorly understood. Here, we uncover widespread DNA hypermethylation in the myeloid compartment of IDH-mutant gliomas, predominantly at distal enhancers enriched for motifs of core microglial transcription factors (TFs). This remodeled enhancer landscape strongly correlated with reduced activity of TF regulons and coordinated repression of immunomodulatory programs that normally support microglial activation. Using primary human microglia, we show that prolonged exposure to the oncometabolite D-2-hydroxyglutarate (D-2HG) reduces TET activity and increases 5mC/5hmC ratios near TF-binding motifs within enhancers affected ex vivo. Consistent with these epigenetic alterations, D-2HG-treated microglia exhibited transcriptional signatures compatible with blunted proinflammatory responses, whereas pharmacological inhibition of mutant IDH in patients partially restored microglial immune reactivity. Altogether, our findings reveal a chronic D-2HG-driven epigenetic priming mechanism that promotes a hyporesponsive microglial state, providing a rationale for the immunologically cold phenotype of IDH-mutant gliomas and offering insight into how IDH-targeted therapies may reshape microglial immune responses.

cancer biology↗

bioRxiv2022

Single Cell Spatial Analysis Reveals the Topology of Immunomodulatory Purinergic Signaling in Glioblastoma

Glioblastoma develops an immunosuppressive microenvironment that fosters tumorigenesis and resistance to current therapeutic strategies. Here we use multiplexed tissue imaging and single-cell RNA-sequencing to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioblastoma. We show that glioblastoma exhibit strong expression of CD39 and CD73 ectoenzymes, correlating with increased adenosine levels. Microglia are the predominant source of CD39, while CD73 is principally expressed by tumor cells, particularly in tumors with amplification of EGFR and astrocyte-like differentiation. Spatially-resolved single-cell analyses demonstrate strong spatial correlation between tumor CD73 and microglial CD39, and that their spatial proximity is associated with poor clinical outcomes. Together, this data reveals that tumor CD73 expression correlates with tumor genotype, lineage differentiation, and functional states, and that core purine regulatory enzymes expressed by neoplastic and tumor-associated myeloid cells interact to promote a distinctive adenosine-rich signaling niche and immunosuppressive microenvironment potentially amenable to therapeutic targeting.

cancer biology↗

bioRxiv2021

Pan-cancer landscape of AID-related mutations, composite mutations and its potential role in the ICI response

Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family, may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome or targeted sequencing. AID synergizes initial hotspot mutations by a second composite mutation. Analysis of 2.5 million cells, normal and oncogenic, revealed AICDA expression activation after oncogenic transformation and cell cycle regulation loss. AID mutational load was found to be independently associated with favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2,000 samples. Finally, we found that AID related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity and T-cell exhaustion, which may increase ICI sensitivity. In BriefA combined bulk and single cell multi-omic analysis of over 50,000 patients and 2.5 million cells across 80 tumor types reveals oncogenic acquired AICDA expression inducing composite mutations and clonal immunogenic neoepitopes that are associated with favorable outcome in patients treated by immune-checkpoint inhibitors. Highlights* Pan-cancer analysis of AID mutations using > 50,000 samples, 2,000 ICI treated cases and 2.5 million cells with genome, exome and transcriptome data * Oncogenic transient AICDA expression induces mutations mainly during transcription of its off-target genes in virtually all cancers * AID is implicated in composite mutations on weakly functional alleles and immunogenic clonal neoepitopes at hotspots with greater positive selection * AID mutational load predicts response and is associated with favorable outcome in ICI treated patients

bioinformatics↗

bioRxiv2020

Functional drug susceptibility testing based on biophysical measurements predicts patient outcome in glioblastoma patient-derived neurosphere models

Functional precision medicine aims to match each cancer patient to the most effective treatment by performing ex vivo drug susceptibility testing on the patients tumor cells. Despite promising feasibility studies, functional drug susceptibility testing is not yet used in clinical oncology practice to make treatment decisions. Often, functional testing approaches have measured ex vivo drug response using metabolic assays such as CellTiter-Glo, which measures ATP as a proxy for numbers of viable cells. As a complement to these existing metabolic drug response assays, we evaluated whether biophysical assays based on cell mass (the suspended microchannel resonator mass assay) or size as measured by microscopy (the IncuCyte assay) could be used as a readout for ex vivo drug response. Using these biophysical assays, we profiled the ex vivo temozolomide responses of a retrospective cohort of 70 glioblastoma patient-derived neurosphere models with matched clinical outcomes and found that both biophysical assays predicted patients overall survival with similar power to MGMT promoter methylation, the clinical gold standard biomarker for predicting temozolomide response in glioblastoma. These findings suggest that biophysical assays could be a useful complement to existing metabolic approaches as "universal biomarkers" to measure sensitivity or resistance to anti-cancer drugs with a wide variety of cytostatic or cytotoxic mechanisms. One-sentence summaryBy using biophysical assays to perform ex vivo drug susceptibility testing on 70 glioblastoma patient-derived neurosphere models, we find that functional testing predicts the duration that patients survive when treated with temozolomide, the standard of care chemotherapy.

cancer biology↗