1,721,005 research outputs found
Role of the chemokine receptor CCR2 in the dynamic of regulatory T cells and monocytes/macrophages in response to antitumor therapies
No full textUne forte production de la chimiokine CCL2 par les cellules malignes et les cellules stromales a été démontrée dans la plupart des cancers humains. Ainsi, l’axe chimiokinique CCR2/CCL2 est un important marqueur du développement des cancers ; ce même axe est associé à la récurrence de tumeurs après thérapie anticancéreuses. Les macrophages associés aux tumeurs (TAM) et les lymphocytes T régulateurs (Treg) ont des capacités immunosuppressives robustes et contribue à la croissance tumorale. Durant cette thèse, je me suis intéressé à la fonction de l’expression du récepteur de chimiokine CCR2 par ces cellules dans le contexte de thérapies anticancéreuses. Nous avons montré que le récepteur de chimiokines CCR2 contrôle la migration des Treg en contexte tumoral, chez l’homme et la souris, et que son expression par les Treg peut servir de biomarqueur de la réponse à la chimiothérapie. Notre étude indique une nouvelle fonction de CCR2 et définie un nouveau sous-type de Treg impliqué dans la régulation de l’immunité antitumorale. En parallèle, nous avons pu mettre en évidence que les métastases pulmonaire sont composées à la fois de macrophages résident du tissu et de macrophages recrutés via l’axe CCR2. La présence de macrophages résidents au sein des tumeurs pourrait contribuer à l’hétérogénéité des microenvironnements de diffèrent type de tumeurs. Le récepteur CCR2 est important pour le la phase de rechute après chimiothérapie, indiquant un rôle limité des macrophages résidents dans ce phénomène. De plus, nous avons montré que le VEGF joue un rôle direct dans la survie des TAM. Ainsi, la combinaison de la chimiothérapie avec un anticorps anti-VEGF cible simultanément les TAM résidents et recrutés et permet d’augmenter l’efficacité de la chimiothérapie.Malignant and stromal cells are strong producer of the chemokine CCL2 in most human cancers. The chemokine axis CCR2/CCL2 is thus a key marker of cancer development, but is also associated with relapse following therapy. Tumour associated macrophages (TAM) and regulatory T cells (Treg) display robust immunosuppressive capacities and contribute to tumour growth. My thesis work focused on the function of the expression of the chemokine receptor CCR2 by these cell types in the context of anticancer therapies. We have shown that CCR2 controls the migration of Treg in tumoral context, in both human and mice, and that the expression of this receptor by Treg could serve as a biomarker of the response to chemotherapy. Our study indicate a novel function of CCR2, defining at the same time a new Treg subset implicated in the regulation of antitumor immunity.We have also demonstrated that pulmonary metastases are composed of both tissue resident and recruited macrophages. The presence of resident macrophages within tumours could contribute to the heterogeneity of the microenvironment of different tumour types. CCR2 is largely implicated in the relapse phase following chemotherapy, indicating a limited role for resident macrophages in this phenomenon. Meanwhile, we have demonstrated that VEGF plays a direct role in TAM survival. The combination of chemotherapy with an anti-VEGF antibody targets both resident and recruited TAM, thereby enhancing the efficacy of chemotherapy. Finally, we have shown that the CCR2/CCL2 axis is implicated in the response to radiotherapy by enhancing the recruitment of both Treg and TAM. This work provides evidences for a central role of the CCR2/CCL2 axis in mediating Treg and TAM co-localization in response to anticancer therapy, this axis could also contribute to establishment of immunosuppressive networks in tumours. Our results provide a better understanding of the immune mechanism implicated in resistance to anticancer therapies
Study of mononuclear phagocyte dynamic during the inflammatory process
No full textRésumé des travaux de thèse Contrairement au dogme original décrit par van Furth sur le système des phagocytes mononucléés (MP), il est maintenant suggéré que les monocytes ne représentent plus uniquement des précurseurs de macrophages mais qu'ils exercent des fonctions immunologiques en tant que tel. Non seulement les monocytes sont capables de circuler dans les tissus sans se différencier en macrophages mais la plupart des macrophages tissulaires ont en réalité une origine embryonnaire. Je me suis intéressée à l'activité migratoire et aux fonctions effectrices des monocytes et des macrophages grâce à l'utilisation de l'imagerie intravitale. Cette approche nous a permis d'appréhender la dynamique des MP entre le réseau vasculaire et le parenchyme tissulaire. De cette façon nous avons pu mettre en évidence le rôle de CX3CR1 dans le contrôle du déploiement monocytaire dans un modèle d'inflammation aiguë. En parallèle, dans un modèle de métastases pulmonaires, nous avons démontré que les monocytes ne contribuent qu'à une partie des macrophages associés aux tumeurs (TAM) et que l'autre partie dérive de la prolifération des macrophages interstitiels du poumon. Ces différentes sous-populations de TAM semblent avoir des contributions différentes dans le développement tumoral et la réponse à la chimiothérapie. Mon travail a permis de mieux appréhender la biologie des monocytes au-delà de leur fonction comme simples précurseurs de macrophages et apportent des concepts nouveaux sur l'origine des TAM. Ces travaux ouvrent de nouvelles perspectives dans la compréhension des mécanismes biologiques gouvernés par les MP et dans la régulation la réponse inflammatoire.Contrariwise to the original dogma established by van Furth on the Mononuclear Phagocyte System (MPs), it is now suggested that monocyte fate and functions should not be restricted to macrophage precursors. Experimental evidences show that monocytes can circulate in tissues without differentiating and most of the tissue associated macrophages have embryonic origin. My thesis work focused on migratory activity and effective functions of monocytes and macrophages based on intravital imaging technology. This approach represent a unique tool to study the dynamic of MPs between the vasculature and tissue parenchyma. Our work provided new insights in the role of CX3CR1 in the monocyte deployment during acute inflammatory response.In a model of pulmonary metastases, we also demonstrated that monocytes represent only one part of tumor associated macrophages (TAMs) and the other part is constituted by lung interstitial macrophages. These different subsets of TAMs seem to contribute differently in tumor development and response to chemotherapy.Overall my work provides new insights about monocyte biology beyond their macrophage precursor fate and presents new concepts on the origin of TAMs. It also adds new perspectives in the understanding of biological mechanism regulated by MPs and in the control of the inflammatory response
Altered peripheral blood monocyte phenotype and function in chronic liver disease: implications for hepatic recruitment and systemic inflammation
Full text linkBackground and Aim
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Study of the modulation of macrophage niches during tumor development and in response to chemotherapy
No full textLes macrophages représentent la population la plus abondante dans la tumeur et leur accumulation est associée à un mauvais pronostic dans beaucoup de cancers. Ils forment un ensemble de sous-populations pouvant varier en termes d’origine, de localisation et de fonction. Ces caractéristiques, définissant l’interaction entre le macrophage et son environnement, forment la niche du macrophage. Les niches de macrophages ont été largement décrites dans les différents tissus à l’homéostasie mais leur évolution dans la tumeur est mal connue. Mon projet de thèse s’intéresse à caractériser les niches de macrophages et s’articule autour de deux projets ; l’évolution des niches de macrophages lors du développement tumoral ; et l’impact de la chimiothérapie sur les niches de macrophages, en particulier le rôle des Treg dans la polarisation de celles-ci. A travers ces projets, nous mettons en évidence que l’hétérogénéité des macrophages est directement associée à la diversité des niches spatiales définies dans la tumeur. La polarisation des macrophages est dictée par les signaux de ces niches. Nous suggérons également que la chimiothérapie favorise les interactions entre Treg et macrophages dans la tumeur, que la déplétion des Treg post-chimiothérapie conduit à une repolarisation des macrophages vers un phénotype pro-inflammatoire, associée à un contrôle de la croissance tumorale. Ce travail met en évidence l’importance de la relation du macrophage avec la tumeur dans l’induction de ses fonctions et pourrait permettre d’identifier les populations à cibler pour rétablir une réponse immunitaire anti-tumorale efficace.Macrophages represent the most abundant population within the tumor and their accumulation is associated with bad prognosis in most cancers. They form a group of sub-populations that vary in terms of origin, localization and function. Those characteristics, defining the interaction between the macrophage and its environment, constitute the macrophage niche. Macrophage niches have been described in different tissues at homeostasis but their evolution during tumor development remains to be elucidated. My thesis project aims at characterizing macrophage niches and focuses on two parts; the evolution of macrophage niches during tumor development; and the impact of chemotherapy on macrophage niches, and specifically the role of Treg on their polarization in this setting. Through those projects, we highlight that the heterogeneity of macrophages is directly linked to the diversity of tumor spatial niches. Macrophage polarization is dictated by signals derived from the niche. We also suggest that chemotherapy favors Treg and macrophage interactions, and that Treg depletion post-chemotherapy leads to the repolarization of macrophages towards a pro-inflammatory phenotype, associated with better tumor control. This work sheds light on the importance of the relationship between the macrophage and the tumor for the induction of its functions, and could identify specific populations to target to restore an efficient anti-tumor immune response
Tracking the Spatial and Functional Gradient of Monocyte-To-Macrophage Differentiation in Inflamed Lung.
Full text linkMyeloid-derived cells such as monocytes, dendritic cells (DCs), and macrophages are at the heart of the immune effector function in an inflammatory response. But because of the lack of an efficient imaging system to trace these cells live during their migration and maturation in their native environment at sub-cellular resolution, our knowledge is limited to data available from specific time-points analyzed by flow cytometry, histology, genomics and other immunological methods. Here, we have developed a ratiometric imaging method for measuring monocyte maturation in inflamed mouse lungs in situ using real-time using 2-photon imaging and complementary methods. We visualized that while undifferentiated monocytes were predominantly found only in the vasculature, a semi-differentiated monocyte/macrophage population could enter the tissue and resembled more mature and differentiated populations by morphology and surface phenotype. As these cells entered and differentiated, they were already selectively localized near inflamed airways and their entry was associated with changes in motility and morphology. We were able to visualize these during the act of differentiation, a process that can be demonstrated in this way to be faster on a per-cell basis under inflammatory conditions. Finally, our in situ analyses demonstrated increases, in the differentiating cells, for both antigen uptake and the ability to mediate interactions with T cells. This work, while largely confirming proposed models for in situ differentiation, provides important in situ data on the coordinated site-specific recruitment and differentiation of these cells and helps elaborate the predominance of immune pathology at the airways. Our novel imaging technology to trace immunogenic cell maturation in situ will complement existing information available on in situ differentiation deduced from other immunological methods, and assist better understanding of the spatio-temporal cellular behavior during an inflammatory response
Impact of anti-cancer therapies on tumor-associated macrophages
No full textLes thérapies conventionnelles, telles que la chimiothérapie, demeurent la principale ligne d'intervention pour la majorité des cas de cancer, malgré des effets secondaires importants et un taux de récidive élevé. Les macrophages associés aux tumeurs (TAM) et les lymphocytes T régulateurs (Treg) sont en partie responsables de l'échec thérapeutique en raison de leur effet immunosuppresseur. Comprendre les processus de résistance aux thérapies liés à la reconstitution de l'axe anti-inflammatoire et immunosuppresseur porté par les TAM et les Treg est essentiel pour éviter ces rechutes. Mon projet de thèse vise à comprendre l'impact des thérapies anticancéreuses sur les macrophages associés aux tumeurs et s'articule autour de deux axes : la caractérisation des macrophages dans les organes en condition d'homéostasie, ainsi que l'impact de la chimiothérapie sur les macrophages associés aux tumeurs et le rôle de leurs interactions avec les Treg dans la récupération de l'immunosuppression. Dans le cadre du premier projet, nous montrons que l'hétérogénéité des macrophages résidant dans les tissus à l'homéostasie est dictée par la composition du tissu au niveau sous-anatomique et que chaque sous-ensemble est régulé par une combinaison distincte de facteurs moléculaires. Dans le cadre du second projet, nous montrons que la chimiothérapie induit des modifications importantes dans le compartiment des macrophages associés aux tumeurs, tant dans les cancers du poumon non à petites cellules chez l'homme que dans un modèle murin. Nous mettons en évidence que les Treg régulent l'équilibre entre monocytes et TAM après la chimiothérapie, favorisant une polarisation anti-inflammatoire. De plus, une thérapie combinant chimiothérapie et anticorps anti-TNFR2 perturbe ces interactions, induisant une réponse pro-inflammatoire des TAM et augmentant la survie des souris dans les modèles tumoraux.Conventional therapies, such as chemotherapy, remain the primary intervention for the majority of cancer cases, despite significant side effects and a high recurrence rate. Tumor-associated macrophages (TAM) and regulatory T cells (Treg) are partly responsible for therapeutic failure due to their immunosuppressive effects. Understanding the processes of resistance to therapies related to the reconstitution of the anti-inflammatory and immunosuppressive axis mediated by TAM and Treg is essential to prevent these relapses. My doctoral project aims to understand the impact of anticancer therapies on TAM and is structured around two axes: the characterization of macrophages in organs under homeostasis, as well as the impact of chemotherapy on TAM and the role of their interactions with regulatory T cells in the recovery of immunosuppression. In the first project, we demonstrate that the heterogeneity of macrophages residing in tissues under homeostasis is dictated by the tissue composition at the sub-anatomical level, and that each subset is regulated by a distinct combination of molecular factors. In the second project, we show that chemotherapy induces significant changes in the compartment of tumor-associated macrophages, both in non-small cell lung cancers in humans and in a murine model. We highlight that regulatory T cells regulate the balance between monocytes and macrophages after chemotherapy, promoting an anti-inflammatory polarization. Furthermore, a therapy combining chemotherapy with anti-TNFR2 antibodies disrupts these interactions, inducing a pro-inflammatory response in tumor-associated macrophages and increasing survival in mouse tumor models
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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