Biology subjects

Antonelli, M.

Publications and source records attributed to Antonelli, M..

5 recordsLinked to original sources

bioRxiv2026

Optimized dosing of spatially heterogeneous radiopharmaceutical therapy reprograms poorly immunogenic tumors to enhance response to immune checkpoint blockade

Immune checkpoint inhibitors (ICIs) are ineffective in patients with poorly immunogenic tumors due to exclusion or exhaustion of effector T cells in the tumor microenvironment (TME) and/or inadequate priming of tumor-specific T cells. Preclinical and clinical studies suggest that radiopharmaceutical therapy (RPT) may overcome such challenges, but an optimal approach to RPT dosing has not been clarified in combination with ICIs. Conventional RPT dosimetry emphasizes mean absorbed radiation doses in tumors and normal tissues, neglecting the spatial distribution of this dose in the TME. We hypothesize that RPT dose heterogeneity in tumors may be leveraged to initiate spatially restricted immuno-radiobiological effects in TME that potentiate antitumor immunity when injecting an activity that delivers high dose (V10%>20 Gy) while also preserving low dose regions (V90%<2.5 Gy) in the TME and not inducing systemic lymphopenia. In studies using lutetium-177 RPT in combination with ICIs, administered activities that met these dosimetric optimization metrics occurred at different mean tumor doses for different RPT agents and different models, yet each achieved therapeutic efficacy in poorly immunogenic murine tumors. Spatial transcriptomics at day 7 after RPT revealed heterogeneous distribution of tumor cell markers with distinct dose-response profiles and localization of dendritic cell (DC) migratory markers in regions of moderate/high dose response marker expression. Combination therapy sustained conventional type 1 DC (cDC1) activation in tumor draining lymph nodes and promoted systemic expansion of antigen-specific CD8 T cells, while serial biopsies revealed effector T cell recruitment and inflammatory cytokine expression in the TME. Optimized intratumoral dose heterogeneity may enable and predict response to ICIs when combined with RPT in tumors not responding adequately to ICIs alone.

cancer biology↗

bioRxiv2026

Intratumoral dose heterogeneity promotes adaptive anti-tumor immunity and predicts clinical response to radiopharmaceutical therapy

Radiopharmaceutical therapies (RPT) deliver non-uniform radiation dose in tumors and the impact of this on response is poorly understood. Dose heterogeneity could engender treatment resistance in low dose regions, yet we hypothesize that a broader array of dose-dependent immuno-radiobiological mechanisms in tumor microenvironments (TME) and preservation of immune function in low-dose regions could promote adaptive anti-tumor immunity and response. In murine models, non-uniform lutetium-177 delivering <2.5 Gy to >20 Gy in a TME induced broader immunomodulatory effects and T cell-dependent survival improvement compared to more uniform distributions. Preserving low-dose regions promoted dendritic cell activation and TME infiltration of clonally expanded CD8+ T cells. In three independent cohorts of patients with prostate cancer, heterogeneous tumor dose distribution strongly correlated with improved clinical outcomes. These findings defy expected radiobiological dose-response and define a novel mechanism of action for RPT, supporting clinical investigation of dose distribution for optimizing patient selection and personalized dosing.

cancer biology↗

bioRxiv2024

A cautionary tale on the cost-effectiveness of collaborative AI in real-world medical applications.

Federated learning (FL) has gained wide popularity as a collaborative learning paradigm enabling trustworthy AI in sensitive healthcare applications. Never-theless, the practical implementation of FL presents technical and organizational challenges, as it generally requires complex communication infrastructures. In this context, consensus-based learning (CBL) may represent a promising collaborative learning alternative, thanks to the ability of combining local knowledge into a federated decision system, while potentially reducing deployment over-head. In this work we propose an extensive benchmark of the accuracy and cost-effectiveness of a panel of FL and CBL methods in a wide range of collaborative medical data analysis scenarios. Our results reveal that CBL is a cost-effective alternative to FL, providing comparable accuracy and significantly reducing training and communication costs. This study opens a novel perspective on the deployment of collaborative AI in real-world applications, whereas the adoption of cost-effective methods is instrumental to achieve sustainability and democratisation of AI by alleviating the need for extensive computational resources.

bioinformatics↗

bioRxiv2023

Identification of a Hypoxia-induced Inflammatory Cell Death Pathway

Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an [~]600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. Here we report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-{kappa}B activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. CYLD-deleted HER2+ cell-derived xenografts phenocopy the effects of PTP1B deficiency, and reconstituting RNF213 knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning "cold" tumors "hot". Our findings also reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders.

cancer biology↗

bioRxiv2022

Identifying eukaryotes in drinking water metagenomes and factors influencing their biogeography.

The biogeography of eukaryotes in drinking water systems is poorly understood relative to prokaryotes or viruses. A common challenge with studying complex eukaryotic communities from natural and engineered systems is that the metagenomic analysis workflows are currently not as mature as those that focus on prokaryotes or even viruses. In this study, we benchmarked different strategies to recover eukaryotic sequences and genomes from metagenomic data and applied the best-performing workflow to explore eukaryotic communities present in drinking water distribution systems (DWDSs). We developed an ensemble approach that exploits k-mer and reference-based strategies to improve eukaryotic sequence identification from metagenomes and identified MetaBAT2 as the best performing binning approach for clustering of eukaryotic sequences. Applying this workflow on the DWDSs metagenomes showed that eukaryotic sequences typically constituted a small proportion (i.e., <1%) of the overall metagenomic data. Eukaryotic sequences showed higher relative abundances in surface water-fed and chlorine disinfected systems. Further, the alpha and beta-diversity of eukaryotes were correlated with prokaryotic and viral communities. Finally, a co-occurrence analysis highlighted clusters of eukaryotes whose presence and abundance in DWDSs is affected by disinfection strategies, climate conditions, and source water types. SynopsisAfter benchmarking tools and developing a dedicated consensus workflow for eukaryotic sequence detection in metagenomes, the experimental, environmental, and engineering factors affecting their biogeography in drinking water distribution systems were investigated Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/518372v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1ae8423org.highwire.dtl.DTLVardef@653471org.highwire.dtl.DTLVardef@5606b7org.highwire.dtl.DTLVardef@1d30cde_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗