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 five 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, 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

Nanophysical and pharmacological approaches to modulate tumor stiffness, extracellular matrix organization and immune response of solid tumors

Le développement de thérapies efficaces pour les tumeurs solides est aujourd'hui fortement mis à l'épreuve par l'hétérogénéité tumorale. Cette hétérogénéité est reliée à la complexité du microenvironnement tumoral (MET) composé de la matrice extracellulaire (MEC), des cellules stromales et immunitaires. Les différentes composantes du MET et leurs interactions jouent un rôle important dans la progression tumorale et la résistance aux thérapies. En particulier, la matrice extracellulaire (MEC) principalement secrétée par les fibroblastes associés au cancer, est caractérisé par une accumulation excessive et une linéarisation anormale des fibres de collagène. Cette architecture aberrante induit une rigidification de beaucoup de tumeurs solides et dresse une barrière physique bloquant la pénétration des chimiothérapies. La réponse immune au développement tumoral est elle aussi influencée par les propriétés mécaniques de la MEC, en particulier la migration des cellules T, ce qui pourrait expliquer le faible taux de réponse aux immunothérapies dans les tumeurs solides. C'est pourquoi nous faisons l'hypothèse que moduler l'organisation de la MEC et sa dureté par des méthodes physiques ou pharmacologiques pourrait permettre d'augmenter l'efficacité de la réponse immune contre les tumeurs. La première partie de cette thèse décrit différents modèles de tumeurs solides dans le but de mettre en relation la rigidité tumorale mesurée par imagerie de manière non invasive avec l'architecture de la tumeur et de son microenvironnement. Afin de modifier l'organisation de la matrice, nous proposons une approche pharmacologique basée sur l'inhibition de l'enzyme lysyl oxidase (LOX), responsable de la réticulation du collagène. Un étude multi échelle a été réalisé sur les différents modèles de tumeur solides pour évaluer l'effet de l'inhibition de LOX sur la rigidité tumorale, la structure du collagène, la croissance tumorale et la migration de cellules T. Nous montrons que l'inhibition de LOX entrainent une diminution de la rigidité de la tumeur et des modifications de l'architecture de la MEC tumorale. Ces changements sont associés à une augmentation de la motilité des lymphocytes T dans les tumeurs et la transformation d'un environnement immunosuppresseur à un environnement immunostimulateur capable de ralentir la progression tumorale. La deuxième partie de cette thèse s'intéresse à la thérapie photothermique (PTT) activée par illumination de nanoparticules d'oxyde de fer en tant qu'approche physique pour moduler le microenvironnement tumoral. Plusieurs types de nanostructures ont été évalués pour cibler les différents composants du microenvironnement de manière contrôlée dans le temps et dans l'espace. Nous avons montré que les nanofleurs d'oxyde de fer décorées à l'or (GIONF) permettent de cibler efficacement les fibroblastes associés au cancer dans un modèle de cholangiocacinome et que la PTT dans ce modèle conduit à une déplétion en fibroblastes, une diminution de la rigidité et une régression du volume tumoral. Par ailleurs, la PTT médiée par ces GIONF a également permis de moduler la réponse immunitaire tumorale dans un modèle de cancer du sein. Enfin, nous avons évalué comment l'auto-organisation de nanoparticules d'oxyde de fer sous forme de structures supra-cristallines plus ou moins déformables pouvait permettre d'induire et de mieux contrôler des effets locaux de l'hyperthermie à l'intérieur des cellules ou dans la matrice extracellulaire.The development of effective therapies for solid tumors is nowadays highly challenged by tumor heterogeneity. This heterogeneity is exacerbated by the complexity of the tumor microenvironment (TME), composed of the extracellular matrix (ECM), stromal and immune cells. The different components of the TME are considered to play an important role in tumor progression and therapeutic resistance. In particular, tumor ECM which is mainly secreted by cancer associated fibroblasts (CAFs), is characterized by an excessive accumulation and linearization of collagen fibers. This aberrant architecture of collagen fibers induces tumor stiffening and confers a physical barrier that blocks chemotherapy penetration into the tumor tissue. The immune response to tumor development is also influenced by the mechanical properties of the tumor ECM, in particular T cell migration, which could explain the low response-rate of immunotherapies in solid tumors. We thus hypothesize that modulating ECM organization and tumor stiffness by nanophysical and pharmacological strategies could improve antitumor immune response and clinical outcome of cancer therapy. The first part of this thesis describes different solid tumor models in order to correlate the tumor stiffness as a non-invasive imaging biomarker to some specific architecture of the TME. We then implemented a pharmacological approach to target the tumor ECM based on the inhibition of the lysyl oxidase (LOX), an enzyme responsible for collagen I crosslinking, and assessed the consequences of LOX inhibition on tumor stiffness, collagen structure, tumor growth and T cell migration in the different tumor models. Results indicate that LOX inhibition led to a decrease in tumor stiffness and alterations in ECM architecture. These changes were associated with an increased motility of T cells in tumors and a switch from an immunosuppressive to immunostimulatory tumor environment that slows down tumor growth. The second part of this thesis focuses on nanoparticle-based photothermal therapy (PTT), as a physical approach to target the tumor ECM. A screen for suitable nanomaterials as agents for PTT was performed in order to select several iron oxide nanostructures to affect the different components of the TME with enhanced spatial and temporal control. Gold decorated iron oxide nanoflowers (GIONF) allow CAF-targeted PTT in a model of choloangiocarcinoma resulting in CAF depletion, reversion of tumor stiffening and tumor regression. GIONF-mediated PTT also allowed the modulation of the tumor immune response in a breast cancer model. Finally, we propose supracristalline self-assemblies of iron oxide nanoparticles in order to trigger well controlled local effect of nanohyperthermia and allow the modulation of PTT effects in solid tumors

Obstacles to T cell migration in the tumor microenvironment

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Patient-reported outcome measures in endometriosis

International audiencePatient Reported Outcome Measures (PROM) evoke measurements that allow capturing patients’ perspectives on their condition. In endometriosis care, physicians’ understanding of the effect of the disease and the treatment on patients is often poor. The use of PROMs in endometriosis clinical practice can facilitate patient-provider communication and the implementation of patient-centered care, improve patients’ quality of life, as well as provide a tool for patients’ self-management of the disease. Today, PROMs are extensively used in research and clinical trials, however they are barely used in clinical practice. The development of digital tools facilitating capturing PROMs can contribute to their use by physicians in routine endometriosis care. However, all PROMs are not adapted to be used in routine care in the context of endometriosis. The objective of this study was to present a catalogue of available PROMs for routine endometriosis care and evaluate them according to selected criteria. To do so, we explored the different PROMs currently in the literature. Consequently, 48 PROM were identified as tools used to evaluate various dimensions of the impact of endometriosis on patients. The selected PROMs were evaluated for their potential to be used as a standard in clinical practice in endometriosis. The selected catalogue of PROMs is the starting point for the integration of digital tools to capture PROMs and the development of patient-centered dashboards to be used by patients and clinicians in endometriosis care and self-management to improve care processes, patient satisfaction, quality of life, and outcomes

Two step promotion of a hot tumor immune environment by gold decorated iron oxide nanoflowers and light-triggered mild hyperthermia

International audiencePhotoactivated Gold decorated iron oxide nanoflowers induce a hot tumor immune microenvironnment in triple negative breast cancer model

Tailored ultra-small Prussian blue-based nanoparticles for MRI imaging and combined photothermal/photoacoustic theranostics

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Intracellular Fate of Hydrophobic Nanocrystal Self‐Assemblies in Tumor Cells

International audienceControl of interactions between nanomaterials and cells remains a biomedical challenge. A strategy is proposed to modulate the intralysosomal distribution of nanoparticles through the design of 3D suprastructures built by hydrophilic nanocrystals (NCs) coated with alkyl chains. The intracellular fate of two water‐dispersible architectures of self‐assembled hydrophobic magnetic NCs: hollow deformable shells (colloidosomes) or solid fcc particles (supraballs) is compared. These two self‐assemblies display increased cellular uptake by tumor cells compared to dispersions of the water‐soluble NC building blocks. Moreover, the self‐assembly structures increase the NCs density in lysosomes and close to the lysosome membrane. Importantly, the structural organization of NCs in colloidosomes and supraballs are maintained in lysosomes up to 8 days after internalization, whereas initially dispersed hydrophilic NCs are randomly aggregated. Supraballs and colloidosomes are differently sensed by cells due to their different architectures and mechanical properties. Flexible and soft colloidosomes deform and spread along the biological membranes. In contrast, the more rigid supraballs remain spherical. By subjecting the internalized suprastructures to a magnetic field, they both align and form long chains. Overall, it is highlighted that the mechanical and topological properties of the self‐assemblies direct their intracellular fate allowing the control intralysosomal density, ordering, and localization of NCs