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Background Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to improve the early graft-versus-leukemia effect mediated by natural killer (NK) cells. Our approach is based on the adoptive transfer of Therapeutic Inducers of Natural Killer cell Killing (ThINKK). ThINKK are expanded and differentiated from HSC, and exhibit blood plasmacytoid dendritic cell (pDC) features. We previously demonstrated that ThINKK stimulate NK cells and control acute lymphoblastic leukemia (ALL) development in a preclinical mouse model of HSCT for ALL. Here, we assessed the cellular identity of ThINKK and investigated their potential to activate allogeneic T cells. We finally evaluated the effect of immunosuppressive drugs on ThINKK-NK cell interaction.Methods ThINKK cellular identity was explored using single-cell RNA sequencing and flow cytometry. Their T-cell activating potential was investigated by coculture of allogeneic T cells and antigen-presenting cells in the presence or the absence of ThINKK. A preclinical human-to-mouse xenograft model was used to evaluate the impact of ThINKK injections on graft-versus-host disease (GvHD). Finally, the effect of immunosuppressive drugs on ThINKK-induced NK cell cytotoxicity against ALL cells was tested.Results The large majority of ThINKK shared the key characteristics of canonical blood pDC, including potent type-I interferon (IFN) production following Toll-like receptor stimulation. A minor subset expressed some, although not all, markers of other dendritic cell populations. Importantly, while ThINKK were not killed by allogeneic T or NK cells, they did not increase T cell proliferation induced by antigen-presenting cells nor worsened GvHD in vivo. Finally, tacrolimus, sirolimus or mycophenolate did not decrease ThINKK-induced NK cell activation and cytotoxicity.Conclusion Our results indicate that ThINKK are type I IFN producing cells with low T cell activation capacity. Therefore, ThINKK adoptive immunotherapy is not expected to increase the risk of GvHD after allogeneic HSCT. Furthermore, our data predict that the use of tacrolimus, sirolimus or mycophenolate as anti-GvHD prophylaxis regimen will not decrease ThINKK therapeutic efficacy. Collectively, these preclinical data support the testing of ThINKK immunotherapy in a phase I clinical trial.

Hicieron falta varias décadas de interacción y diálogo entre las ciencias humanas y las ciencias medioambientales, además de una serie de avances metodológicos, para que los espacios de altura fueran considerados algo más que inmutables y átonos. Sometidos a un cuestionamiento interdisciplinario integrado, revelan no una, sino muchas historias y dinámicas complejas. Historizar las zonas de montaña permite invertir el punto de vista global sobre las sociedades pirenaicas y reconsiderar los sistemas de valles. Es evidente que los equipos que participan en esta línea de investigación se enfrentan al problema de adquirir información primaria. Siendo requisito indispensable de toda investigación arqueológica, la prospección en alta montaña presenta especificidades propias y desafíos metodológicos particulares. Ahora es posible pensar en nuevos procedimientos de adquisición de información arqueológica basados en cinco grandes avances: la diversificación y miniaturización de los sensores, que permiten transportarlos en drones; la reducción significativa de los costes de adquisición de los vehículos aéreos; un entorno de vuelo cada vez más seguro; las herramientas de tratamiento de datos y el trabajo sobre la ergonomía informática, y la apertura de posibilidades que ofrece la inteligencia artificial, que permite prever posibilidades futuras para optimizar la detección de restos arqueológicos en entornos de gran altitud.

ABSTRACTThe annual “Antibody Industrial Symposium”, co-organized by LabEx MAbImprove and MabDesign, held its 10th anniversary edition in Montpellier, France, on June 28–29, 2022. The meeting focused on new results and concepts in antibody engineering (naked, mono- or multi-specific, conjugated to drugs or radioelements) and also on new cell-based therapies, such as chimeric antigenic receptor (CAR)-T cells. The symposium, which brought together scientists from academia and industry, also addressed issues concerning the production of these molecules and cells, and the necessary steps to ensure a strong intellectual property protection of these new molecules and approaches. These two days of exchanges allowed a rich discussion among the various actors in the field of therapeutic antibodies.

Excessive consumption of added sugars is linked to chronic diseases, such as obesity, diabetes, dyslipidaemia or cardiovascular disease; and public health is searching for new strategies to reduce it. Although plant-derived bioactive compounds with inhibitory properties of sweet taste like Gymnema sylvestre show the potential to reduce sugar intake acutely, their impact after repeated administration is unknown. Therefore, we examined the changes of single and repeated exposures of a Gymnema sylvestre constituent, gurmarin, in sweet beverage consumption and preference in a preclinical model. 24 Wistar rats (50 % females) were divided into experimental (gurmarin) and two control groups (gymnemic acids or phosphate buffer solutions) according to the substances orally applied. Then acceptance and preference tests with sugar were performed within (Experiment 1) and between sessions (Experiment 2). We found that administering gurmarin decreased sucrose intake significantly, even after multiple treatments, without rebound effects. These findings suggest that sweet taste suppressors could be an effective tool for reducing long-term sugar consumption when repeatedly administrated.

IntroductionTumor Associated Macrophages (TAM) are a major component of the tumor environment and their accumulation often correlates with poor prognosis by contributing to local inflammation, inhibition of anti-tumor immune response and resistance to anticancer treatments. In this study, we thus investigated the anti-cancer therapeutic interest to target ChemR23, a receptor of the resolution of inflammation expressed by macrophages, using an agonist monoclonal antibody, αChemR23.MethodsHuman GM-CSF, M-CSF and Tumor Associated Macrophage (TAM)-like macrophages were obtained by incubation of monocytes from healthy donors with GM-CSF, M-CSF or tumor cell supernatants (Breast cancer (BC) or malignant pleural mesothelioma (MPM) cells). The effects of αChemR23 on macrophages were studied at the transcriptomic, protein and functional level. Datasets from The Cancer Genome Atlas (TCGA) were used to study CMKLR1 expression, coding for ChemR23, in BC and MPM tumors. In vivo, αChemR23 was evaluated on overall survival, metastasis development and transcriptomic modification of the metastatic niche using a model of resected triple negative breast cancer.ResultsWe show that ChemR23 is expressed at higher levels in M-CSF and tumor cell supernatant differentiated macrophages (TAM-like) than in GM-CSF-differentiated macrophages. ChemR23 activation triggered by αChemR23 deeply modulates M-CSF and TAM-like macrophages including profile of cell surface markers, cytokine secretion, gene mRNA expression and immune functions. The expression of ChemR23 coding gene (CMKLR1) strongly correlates to TAM markers in human BC tumors and MPM and its histological detection in these tumors mainly corresponds to TAM expression. In vivo, treatment with αChemR23 agonist increased mouse survival and decreased metastasis occurrence in a model of triple-negative BC in correlation with modulation of TAM phenotype in the metastatic niche.ConclusionThese results open an attractive opportunity to target TAM and the resolution of inflammation pathways through ChemR23 to circumvent TAM pro-tumoral effects.

Abstract The BAG3- and SIRPα- mediated pathways trigger distinct cellular targets and signaling mechanisms in pancreatic cancer microenvironment. To explore their functional connection, we investigated the effects of their combined blockade on cancer growth in orthotopic allografts of pancreatic cancer mt4–2D cells in immunocompetent mice. The anti-BAG3 + anti-SIRPα mAbs treatment inhibited (p = 0.007) tumor growth by about the 70%; also the number of metastatic lesions was decreased, mostly by the effect of the anti-BAG3 mAb. Fibrosis and the expression of the CAF activation marker α-SMA were reduced by about the 30% in animals treated with anti-BAG3 mAb compared to untreated animals, and appeared unaffected by treatment with the anti-SIRPα mAb alone; however, the addition of anti-SIRPα to anti-BAG3 mAb in the combined treatment resulted in a > 60% (p

A numerous number of positive and negative signals via various molecules modulate T-cell activation. Within the various transmembrane proteins, SIRPγ is of interest since it is not expressed in rodents. SIRPγ interaction with CD47 is reevaluated in this study. Indeed, we show that the anti-SIRPγ mAb clone LSB2.20 previously used by others has not been appropriately characterized. We reveal that the anti-SIRPα clone KWAR23 is a Pan anti-SIRP mAb which efficiently blocks SIRPα and SIRPγ interactions with CD47. We show that SIRPγ expression on T cells varies with their differentiation and while being expressed on Tregs, is not implicated in their suppressive functions. SIRPγ spatial reorganization at the immune synapse is independent of its interaction with CD47. In vitro SIRPα-γ/CD47 blockade with KWAR23 impairs IFN-γ secretion by chronically activated T cells. In vivo in a xeno-GvHD model in NSG mice, the SIRPγ/CD47 blockade with the KWAR23 significantly delays the onset of the xeno-GvHD and deeply impairs human chimerism. In conclusion, we have shown that T-cell interaction with CD47 is of importance notably in chronic stimulation.

Field-walking survey, the historically oldest method of modern archaeology, has undergone little technical development in its field phase. However, the question of the validity and representativeness of the data obtained gave rise to many discussions. The arrival of GPS was a significant improvement in recording capabilities, but remains limited to in-situ recording and analysis. Systematic georeferencing of off-site material has been attempted, but remains experimental, due to the technical complexity it entails, but above all because of its low cost-efficiency in terms of time spent on the documented area. We present an application for mobile phones using the increasingly powerful GPS chips embedded by them. The application allows a real time recording of the trace of a prospector’s path and the artifacts that were observed and collected. The GIS operation of the data collected enables the validity of the measured corpus to be evaluated and an intra-parcel spatial analysis of the surface material to be developed, capable of objectifying the identification of sites, specifying their extent and morphology, while maintaining a good performance of field operations.

Inflammation is a fundamental physiological response orchestrated by innate immune cells to restore tissue homeostasis. Specialized pro-resolving mediators (SPMs) are involved in active resolution of inflammation but when inflammation is incomplete, chronic inflammation creates a favorable environment that fuels carcinogenesis and cancer progression. Conventional cancer therapy also strengthens cancer-related inflammation by inducing massive tumor cell death that activate surrounding immune-infiltrating cells such as tumor-associated macrophages (TAMs). Macrophages are key actors of both inflammation and its active resolution due to their plastic phenotype. In line with this high plasticity, macrophages can be hijacked by cancer cells to support tumor progression and immune escape, or therapy resistance. Impaired resolution of cancer-associated inflammation supported by TAMs may thus reinforces tumor progression. From this perspective, recent evidence suggests that stimulating macrophage’s pro-resolving functions using SPMs can promote inflammation resolution in cancer and improve anticancer treatments. Thus, TAMs’ re-education toward an antitumor phenotype by using SPMs opens a new line of attack in cancer treatment. Here, we review SPMs’ anticancer capacities with special attention regarding their effects on TAMs. We further discuss how this new therapeutic approach could be envisioned in cancer therapy.

The Solar Orbiter (SolO) and Parker Solar Probe missions have opened up new challenges for the heliospheric scientific community. Their proximity to the Sun and their high quality measurements allow us to investigate, for the first time, potential sources for the solar wind plasma measured in situ. More accurate estimates of magnetic connectivities from spacecraft to the Sun are required to support science and operations for these missions. We present a methodology to systematically compare coronal and heliospheric models against white-light (WL) observations. WL images from the SOlar and Heliospheric Observatory (SoHO) are processed to unveil the faint structures of the K-corona. Images are then concatenated over time and are projected into a Carrington synoptic map. Features of interest such as the Streamer Belt (SB) are reduced to simplified geometric objects. Finally, a metric is defined to rank models according to their performance against WL observations. The method has been exploited to reproduce magnetic sectors from WL observations. We tested our results against one year of in situ magnetic polarity measurements taken at near one AU from the Advanced Composition Explorer (ACE) and the Solar TErrestrial RElations Observatory (STEREO-A). We obtained a good correlation that emphasizes the relevance of using WL observations to infer the shape of the sector structure. We show that WL observations provide additional constraints to better select model parameters such as the input photospheric magnetic map. We highlight the capability of this technique to systematically optimize coronal and heliospheric models using continuous and near-real-time WL observations. Several relevant practical applications are discussed, which should allow us to improve connectivity estimates.

The history of land use dynamics can only be written by apprehending a long period of time that transcends academic divisions. It is a necessary step to finely perceive the stages of construction of rural spaces by ancient societies. It requires recourse to a variety of information sources. The difficulties of crossing them are mainly due to the blind spots and the variations in scale and precision, both spatial and chronological, that characterise each of them. In this sense, geographic information systems (GIS) can appear as especially relevant tools to ensure the centralisation, analysis and crossing of information. By emphasising spatial input, the rural historian-archaeologist can deploy the whole range of spatial analysis methods provided by geography. These various challenges are illustrated by the presentation of the first results of the REPERAGE program, which aims to reconstruct the dynamics of the landscape and settlement in the Garonne valley.

The enrichment of coronal loops and the slow solar wind with elements that have low First Ionization Potential, known as the FIP effect, has often been interpreted as the tracer of a common origin. A current explanation for this FIP fractionation rests on the influence of ponderomotive forces and turbulent mixing acting at the top of the chromosphere. The implied wave transport and turbulence mechanisms are also key to wave-driven coronal heating and solar wind acceleration models. This work makes use of a shell turbulence model run on open and closed magnetic field lines of the solar corona to investigate with a unified approach the influence of magnetic topology, turbulence amplitude and dissipation on the FIP fractionation. We try in particular to assess whether there is a clear distinction between the FIP effect on closed and open field regions.

Chronic inflammation often involves reactivation of memory adaptive immune. Here the authors show, using non-human primate models, that a single dose of anti-IL-7 receptor monoclonal antibody that exhibits antagonist but not agonist properties can reduce the frequency of antigen-specific T cell to help repress chronic skin inflammation.

Targeting the expansion of pathogenic memory immune cells is a promising therapeutic strategy to prevent chronic autoimmune attacks. Interleukin 7 (IL-7) is a limiting and potent cytokine produced by epithelial and stromal cells sustaining T-lymphocytes development, homeostasis and cell metabolism. Almost all conventional mature T lymphocytes express the IL-7 receptor (IL-7R), with the exception for naturally-occurring regulatory T-cells (Treg), constituting a rare opportunity to selectively strangle pathogenic effectors while preserving crucial natural regulators. In our recent study, we reported that therapeutic efficacy of antagonist anti- IL-7Rα mAbs in a non-human primate model of memory T cell-induced chronic inflammation depends on recognition of an epitope overlapping the IL-7 binding domain (site 1) and the receptor heterodimerization region (site-2b) (Nat Commun, 9(1):4483). We found that “site-1-only” mAbs prevented IL-7-induced JAK/STAT signaling but induced PI3K and Erk signaling and lacked efficacy in vivo, whereas “site-1 + 2b” mAbs were fully antagonist and demonstrated potent activity to control skin inflammation on the long term. The mechanism of action comprised the neutralization of IFN-γ producing antigen-specific memory T cells, without inducing lymphopenia or polyclonal T-cell functional or metabolic defects as generally observed previously in rodents.

Brazzein is a small sweet-tasting protein found in the red berries of a West African evergreen shrub, Pentadiplandra brazzeana Baillon. Brazzein is highly soluble and stable over a large pH range and at high temperatures, which are characteristics that suggest its use as a natural sweetener. However, Pentadiplandra brazzeana culture is difficult at a large scale, limiting the natural source of brazzein. Heterologous expression of brazzein has been established in numerous systems, including bacteria, yeast, and transgenic plants. Brazzein requires four disulfide bonds to be active in eliciting an intense sweet taste, and the yeast Pichia pastoris appears to be one of the best options for obtaining functional brazzein in high quantities. Employing yeast secretion in the culture medium allows us to obtain fully active brazzein and facilitate purification later. To increase yeast secretion, we compared seven different signal peptides to successfully achieve brazzein secretion using the yeast P. pastoris. The brazzein proteins corresponding to these signal peptides elicited activation of the sweet taste receptor functionally expressed in a cellular assay. Among these tested signal peptides, three resulted in the secretion of brazzein at high levels.

La démocratisation récente des drones engendre une rupture méthodologique en matière de télédétection archéologique. Le premier point concerne la facilité d'utilisation de ces vecteurs, qui fournissent des environnements de vol sécurisés, notamment grâce aux systèmes de navigation GPS et la possibilité de définir des waypoints pour des vols semi-automatisés. Cette flexibilité permet également de répéter des vols sur la même zone. Le deuxième point intéressant pour la télédétection archéologique est la faible altitude de vol des drones, permettant la documentation d'une échelle intermédiaire entre le site et la micro-région. La basse altitude est aussi un moyen d'acquérir des informations de meilleure qualité et de plus grande résolution. Le dernier point concerne le faible coût d'utilisation, même si le prix d'acquisition de l'équipement est assez élevé. Le développement des drones en télédétection archéologique implique donc la définition de nouvelles utilisations pour les capteurs traditionnels. Nous décrivons celles développées dans le cadre du programme toulousain Archéodrones en matière de photogrammétrie et thermographie aéroportée. De nouveaux capteurs seront sans doute adaptés à l'avenir sur drone permettant un accès plus large à ces méthodes de prospection non-invasives.

The advantage of studying long term population processes of agrarian spaces, is being able to asses the part of inheritance that profits each population phase. The notions of opportunism or innovation in the choices made by ancient societies relative to the establishment of settlements or farmed spaces are rarely considered. We thus propose two indicators for the estimation of the opportunism of Medieval societies which, combined with reconstitution of the environmental context, partly explain the different episodes of taking and reliquishing hold of spaces, or the mobility within population patterns and parishes during the Middle Ages.

The effector functions of T lymphocytes are responsible for most autoimmune disorders and act by directly damaging tissues or by indirectly promoting inflammation and antibody responses. Co-stimulatory and co-inhibitory T cell receptor molecules are the primary pharmacological targets that enable interference with immune-mediated diseases. Among these, selective CD28 antagonists have drawn special interest, since they tip the co-stimulation/co-inhibition balance towards efficiently inhibiting effector T cells while promoting suppression by pre-existing regulatory T-cells. After having demonstrated outstanding therapeutic efficacy in multiple models of autoimmunity, inflammation and transplantation, and safety in phase-I studies in humans, selective CD28 antagonists are currently in early clinical development for the treatment of systemic lupus erythematous and rheumatoid arthritis. Here, we review the available proof of concept studies for CD28 antagonists in autoimmunity, with a special focus on the mechanisms of action.

CD28, CTLA-4 and PD-L1, the three identified ligands for CD80/86, are pivotal positive and negative costimulatory molecules that, among other functions, control T cell motility and formation of immune synapse between T cells and antigen-presenting cells (APCs). What remains incompletely understood is how CD28 leads to the activation of effector T cells (Teff) but inhibition of suppression by regulatory T cells (Tregs), while CTLA-4 and PD-L1 inhibit Teff function but are crucial for the suppressive function of Tregs. Using alloreactive human T cells and blocking antibodies, we show here by live cell dynamic microscopy that CD28, CTLA-4, and PD-L1 differentially control velocity, motility and immune synapse formation in activated Teff versus Tregs. Selectively antagonizing CD28 costimulation increased Treg dwell time with APCs and induced calcium mobilization which translated in increased Treg suppressive activity, in contrast with the dampening effect on Teff responses. The increase in Treg suppressive activity after CD28 blockade was also confirmed with polyclonal Tregs. Whereas CTLA-4 played a critical role in Teff by reversing TCR-induced STOP signals, it failed to affect motility in Tregs but was essential for formation of the Treg immune synapse. Furthermore, we identified a novel role for PD-L1-CD80 interactions in suppressing motility specifically in Tregs. Thus, our findings reveal that the three identified ligands of CD80/86, CD28, CTLA-4 and PD-L1, differentially control immune synapse formation and function of the human Teff and Treg cells analyzed here. Individually targeting CD28, CTLA-4 and PD-L1 might therefore represent a valuable therapeutic strategy to treat immune disorders where effector and regulatory T cell functions need to be differentially targeted.

Si le travail est un objet familier des sciences sociales, c’est que, en vertu de ses caractéristiques intrinsèques, il peut fournir à la sociologie l’occasion d’une mise à l’épreuve probante de ses catégories centrales, retrouvant dans l’effort d’une structuration rationnelle de l’agir humain, dont la technique et le travail constituent des expressions privilégiées, la marque de sa rationalité propre. Il n’est en ce sens guère étonnant que le travail, qu’il soit ...

Geolocation of ancient sources is a challenge to historians and archaeologists who aims to adopt a spatial approach to their object of study. Known biases affecting the corpus of sources that have survived can often be considered prohibitive to any spatial approach of their contents. Worse, these same biases, whether related to production conditions, hazards of conservation or vagaries of counting, can discourage any attempt of quantitative analysis of these data. This paper proposes two different aspects of spatial analysis through the implementation of modern and medieval written sources, both of which sharing a common ground investigation. The first part concerns the presentation of a methodology for use of textual citations identified in serial sources in order to highlight the medieval and modern dynamics affecting the landscape and settlement. The second part concerns the study of space standards and organizational models described by the written sources that it is possible to test by the use of spatial analysis tools.