Biology subjects

Sciume, G.

Publications and source records attributed to Sciume, G..

7 recordsLinked to original sources

bioRxiv2025

Preserved suppressive function despite loss of Foxp3: insights into the identity of regulatory T cells

Regulatory T (Treg) cells are essential for maintaining immune homeostasis, with Foxp3 acting as the master transcription factor governing their differentiation and function. The acquisition of effector signatures in Treg cells is closely tied to the surrounding tissue-specific immune environment and typically occurs alongside Foxp3 expression. In this study, we investigated the transcriptomic and functional consequences of Treg-mediated regulation in a Th2-driven disease setting. The application of both in vitro systems and in vivo disease models allowed us to mimic Th2-mediated environments. We could demonstrate Th2-driven loss of Foxp3 expression in Treg cells in vitro and in vivo. Transcriptomic analysis revealed a maintained Treg signature despite the loss of active Foxp3 expression. Functional characterization of Tregs both in vitro and in vivo uncovered a preserved suppressive capacity even in the absence of Foxp3. Our findings unveil that, despite loss of Foxp3, a preserved Treg signature remains intact enabling the regulation of Th2-mediated diseases. The persistence of this regulatory transcriptome highlights the importance for developing Treg-cell therapy strategies in cancer and autoimmune diseases independent of Foxp3 expression.

immunology↗

bioRxiv2024

LAG3 marks activated but hyporesponsive NK cells.

Natural Killer (NK) cells are critical for immunosurveillance yet become dysfunctional in contexts such as chronic stimulation by viral infections or cancer. This phenomenon is similar to T cell exhaustion but less well characterized, which limits therapeutic interventions. As shown for T cells, NK cells often display an increased expression of immune checkpoint proteins (ICP) following chronic stimulation, and ICP blockade therapies are currently being explored for several cancer types, which have remarkable patient benefits. Nevertheless, the nature of ICP expression in NK cells is still poorly documented. In this study, we aimed to identify the conditions that lead to and the phenotype of immune checkpoint LAG3 (Lymphocyte-activation gene 3) expressing NK cells. Using various experimental models, we found that LAG3 is expressed by murine NK cells upon activation in different contexts, including in response to cancer and acute viral infections. LAG3 marks a subset of immature, proliferating and activated cells, which, despite activation, have a reduced capacity to respond to a broad range of stimuli. Further characterization also revealed that LAG3+ NK cells exhibit a transcriptional signature similar to that of exhausted CD8+ T cells. Taken together, our results support the use of LAG3 as a marker of dysfunctional NK cells across diverse chronic and acute inflammatory conditions.

immunology↗

bioRxiv2023

Non-operable glioblastoma: proposition of patient-specific forecasting by image-informed poromechanical model

We propose a novel image-informed glioblastoma mathematical model within a reactive multiphase poromechanical framework. Poromechanics offers to model in a coupled manner the interplay between tissue deformation and pressure-driven fluid flows, these phenomena existing simultaneously in cancer disease. The model also relies on two mechano-biological hypotheses responsible for the heterogeneity of the GBM: hypoxia signaling cascade and interaction between extra-cellular matrix and tumor cells. The model belongs to the category of patient-specific image-informed models as it is initialized, calibrated and evaluated by the means of patient imaging data. The model is calibrated with patient data after 6 cycles of concomitant radiotherapy chemotherapy and shows good agreement with treatment response 3 months after chemotherapy maintenance. Sensitivity of the solution to parameters and to boundary conditions is provided. As this work is only a first step of the inclusion of poromechanical framework in image-informed glioblastoma mathematical models, leads of improvement are provided in the conclusion.

biophysics↗

bioRxiv2022

Programmed cell death-1 receptor mediated regulation of Tbet+ NK1.1- Innate Lymphoid Cells within the Tumor Microenvironment

Innate Lymphoid Cells (ILCs) play a key role in tissue mediated immunity and can be controlled by co-receptor signaling. Here we define a subset of ILCs that are Tbet+NK1.1- and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet+NK1.1-ILCs. PD-1 significantly controlled the proliferation and function of Tbet+NK1.1-ILCs in multiple murine and human tumors. We found tumor derived lactate enhanced PD-1 expression on Tbet+NK1.1-ILCs within the TME, which resulted in dampened mTOR signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1 deficient Tbet+NK1.1-ILCs expressed significantly increased IFN{gamma}, granzyme B and K. Furthermore, PD1 deficient Tbet+NK1.1- ILCs contributed towards diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate anti-tumor responses of Tbet+NK1.1-ILCs within the tumor microenvironment. HighlightsO_LITbet+NK1.1- ILCs are found in WT and PD1 ko mice C_LIO_LIPD-1 is expressed on Tbet+NK1.1- ILC1s within multiple TME C_LIO_LIPD-1 controls the proliferation and function of Tbet+NK1.1- ILCs within the tumor microenvironment by modulating fatty acid metabolism. C_LIO_LIPD-1 regulates the proliferation of human Tbet+ ILC1s in human cutaneous squamous cell carcinoma (cSCC) and melanoma tumor microenvironment. C_LI

immunology↗

bioRxiv2020

Mechanistic modeling of vascular tumor growth: an extension of Biot's theory to hierarchical bi-compartment porous medium system

Existing continuum multiphase tumor growth models typically do not include microvasculature, or if present, this is modeled as non-deformable. Vasculature behavior and blood flow are usually non-coupled with the underlying tumor phenomenology from the mechanical viewpoint; hence, phenomena as vessel compression/occlusion modifying microcirculation and oxygen supply cannot be taken into account. The tumor tissue is here modeled as a reactive bi-compartment porous medium: the extracellular matrix constitutes the solid scaffold; blood is in the vascular porosity whereas the extra-vascular porous compartment is saturated by two cell phases and interstitial fluid (mixture of water and nutrient species). The pressure difference between blood and the extra-vascular overall pressure is sustained by vessel walls and drives shrinkage or dilatation of the vascular porosity. Model closure is achieved thanks to a consistent non-conventional definition of the Biots effective stress tensor. Angiogenesis is modeled by introducing a vascularization state variable, and accounting for tumor angiogenic factors and endothelial cells. Closure relationships and mass exchange terms related to vessel formation are detailed in a numerical example reproducing the principal features of angiogenesis. This example is preceded by a first pedagogical numerical study on one-dimensional bio-consolidation. Results are exquisite to realize that the bi-compartment poromechanical model is fully coupled (the external loads impact fluid flow in both porous compartments) and to envision further applications as for instance modeling of drugs delivery and tissue ulceration.

biophysics↗

bioRxiv2020

NK cells acquire PD-1 from the membrane of tumor cells.

Leucocytes often perform trogocytosis, the process by which cells acquire parts of the plasma membrane from interacting cells. Accumulating evidence indicates that trogocytosis modulates immune responses, but the underlying molecular mechanisms are unclear. Here, using two mouse models of leukemia, we found that cytotoxic lymphocytes perform trogocytosis at high rates with tumor cells. While performing trogocytosis, both Natural Killer and CD8+ T cells acquire the checkpoint receptor PD-1 from leukemia cells. In vitro and in vivo investigation revealed that PD-1 protein found on the surface of Natural Killer cells, rather than being endogenously expressed, was derived entirely from leukemia cells. Mechanistically, SLAM receptors were essential for PD-1 trogocytosis. PD-1 acquired via trogocytosis actively suppressed anti-tumor immunity, as revealed by the positive outcome of PD-1 blockade in PD-1-deficient mice. PD-1 trogocytosis was corroborated in patients with clonal plasma cell disorders, where Natural Killer cells that stained for PD-1 also stained for tumor cell markers. Our results, in addition to shedding light on a previously unappreciated mechanism underlying the presence of PD-1 on Natural Killer and cytotoxic T cells, reveal the immune-regulatory effect of membrane transfer occurring when immune cells contact tumor cells. Once sentence summaryNatural Killer cells are inhibited by PD-1 acquired from the surface of tumor cells via trogocytosis.

immunology↗

bioRxiv2020

Quantifying the role of mechanics in the free and encapsulated growth of cancer spheroids

Spheroids encapsulated within alginate capsules are emerging as suitable in vitro tools to investigate the impact of mechanical forces on tumor growth since the internal tumor pressure can be retrieved from the deformation of the capsule. Here we focus on the particular case of Cellular Capsule Technology (CCT). We show in this contribution that a modeling approach accounting for the triphasic nature of the spheroid (extracellular matrix, tumor cells and interstitial fluid) offers a new perspective of analysis revealing that the pressure retrieved experimentally cannot be interpreted as a direct picture of the pressure sustained by the tumor cells and, as such, cannot therefore be used to quantify the critical pressure which induces stress-induced phenotype switch in tumor cells. The proposed multiphase reactive poro-mechanical model was cross-validated. Parameter sensitivity analyses on the digital twin revealed that the main parameters determining the encapsulated growth configuration are different from those driving growth in free condition, confirming that radically different phenomena are at play. Results reported in this contribution support the idea that multiphase reactive poro-mechanics is an exceptional theoretical framework to attain an in-depth understanding of CCT experiments, to confirm their hypotheses and to further improve their design.

biophysics↗