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Cascone, I.

Publications and source records attributed to Cascone, I..

3 recordsLinked to original sources
bioRxiv2025

QUANTITATIVE PROTEOMICS OF PLASMA EXTRACELLULAR VESICLES REVEALS A TTR - PLASMINOGEN NETWORK IN ATTR CARDIAC AMYLOIDOSIS

BackgroundDespite recent progress, the prognosis of patients with transthyretin (TTR) cardiac amyloidosis remains poor; this is primarily due to late diagnosis, when irreversible damage has already occurred. Todays diagnostic work-up still relies on peripheral tissue or a cardiac biopsy, while circulating levels of TTR or other plasma markers have little diagnostic value. Although extracellular vesicles (EVs, as key mediators of intercellular communication) may reflect disease-specific molecular changes, their protein cargo has not yet been explored in the context of TTR amyloidosis (ATTR) cardiomyopathy. ObjectivesTo characterize the plasma EV proteome in ATTR cardiomyopathy and identify potential biomarkers for pathophysiological pathways, diagnosis, or prognosis. MethodsWe performed mass-spectrometry-based, label-free, proteomic profiling of plasma EVs from 65 patients with hypertrophic cardiomyopathy due to TTR amyloidosis (the ATTR+ group, n=41) or non-amyloid cardiac disease (the ATTR- group, n=24). The groups were matched by age and sex. ResultsA distinct protein signature comprising 117 deregulated proteins was identified in EVs from ATTR+ patients. The ATTR+ EVs were enriched in proteins associated with vascular homeostasis, coagulation, and inflammation. At least 18 of these proteins formed an interconnected network centered on plasmin/plasminogen. Notably, EV levels of TTR and plasminogen levels were elevated, while the level of alpha2-antiplasmin (plasmins primary inhibitor) was low. This imbalance is particularly relevant because plasmin is known to promote amyloidogenesis via TTR cleavage. ConclusionsOur findings provide new insights into the molecular mechanisms underlying ATTR cardiomyopathy and suggest that plasma EV proteins are potential diagnostic or prognostic biomarkers and/or therapeutic targets. CONDENSED ABSTRACTTTR amyloidosis (ATTR) causes severe cardiac damage, which is often diagnosed late. Through a comparative proteomic analysis of plasma extracellular vesicles (EVs) in patients with ATTR cardiomyopathy vs. patients with other cardiomyopathies, we identified several proteins of relevance to the pathophysiology of ATTR. Our analysis is the first to have highlighted an enrichment of plasmin/plasminogen (known to initiate the amyloidogenic process) and TTR in circulating EVs. Our results might foster the development of (i) diagnostic and prognostic markers for ATTR cardiomyopathy that do not require invasive procedures, and (ii) new therapeutic strategies. CENTRAL ILLUSTRATION - GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/662124v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@e64a55org.highwire.dtl.DTLVardef@11a1f38org.highwire.dtl.DTLVardef@1f7b1cborg.highwire.dtl.DTLVardef@b990aa_HPS_FORMAT_FIGEXP M_FIG C_FIG ETHICAL APPROVALThe present analysis was based on blood samples collected as part of a research project entitled "Study of the myocardial microenvironment and toxicity of amyloid proteins in patients with cardiac amyloidosis", which was approved by an institutional review board (CPP Sud- Mediterranee II, Marseille, France; approval references: 2021T2-12/2021-A00950-41 and 2022-A02416-37).

biochemistry↗
bioRxiv2024

TNFR2 blockade promotes anti-tumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing TNF receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in PDAC patients. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing anti-tumoral responses. MethodTo support this hypothesis, we first described TNFR2 expression in a cohort of 24 PDAC patients from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as effect on tumor progression. ResultsPDAC patients exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells but low level in ductal cells. By flow cytometry and single cell RNAseq analysis, we identified two Treg populations in orthotopic mouse models: resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+ T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8+ T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAbs promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice. ConclusionOur data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for PDAC patients.

immunology↗
bioRxiv2020

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing 5 preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase (LOX) was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

cancer biology↗