L'absence de CD226 caractérise des LT CD8+ hyporépondeurs au TCR et aux fonctions antitumorales défectueuses

Les lymphocytes cytotoxiques T CD8+ (LT CD8+) sont des cellules de l'immunité adaptative qui jouent un rôle majeur dans les réponses immunitaires antitumorales puisqu'ils reconnaissent et tuent spécifiquement les cellules cancéreuses. Cependant, leurs fonctions antitumorales sont souvent limitées par l'expression de récepteurs inhibiteurs tels que CTLA-4 et PD-1. Bien que les immunothérapies basées sur le blocage de ces récepteurs représentent l'une des avancées majeures dans le traitement du cancer, de nombreux cancers y sont réfractaires. Ainsi, il est aujourd'hui nécessaire de comprendre davantage les mécanismes à l'origine de cette résistance thérapeutique et d'identifier d'autres cibles régulant les fonctions antitumorales des LT CD8+. Tandis que les stratégies immunothérapeutiques actuelles se concentrent essentiellement sur l'identification d'autres récepteurs inhibiteurs, le rôle des récepteurs activateurs des LT CD8+ dans la réponse aux immunothérapies reste encore peu approfondi. Initialement décrite comme une molécule d'adhésion, CD226 (DNAM-1) est un récepteur coactivateur exprimé par les cellules NK et les LT CD8+ qui stimule leur production de cytokines inflammatoires et de granules cytolytiques vis-à-vis de cellules cibles suite à son interaction avec ses ligands CD112 et CD155. La nectine CD112 et la "nectine-like" CD155 sont fréquemment exprimées par les cellules tumorales et des modèles murins immunodéficients CD226-/- ont pu démontrer que CD226 joue rôle critique dans l'immunosurveillance antitumorale. Par ailleurs, les récepteurs inhibiteurs TIGIT et CD96 qui rentrent en compétition avec CD226 ont récemment été caractérisés comme des cibles d'immunothérapies intéressantes, ce qui renforce l'idée selon laquelle la réponse immunitaire antitumorale est régulée par CD226. Au cours de ma thèse, j'ai mis en évidence que CD226 identifie les populations LT CD8+ CD226- et LT CD226+ chez des individus sains et des patients atteints de cancer. Des analyses transcriptomiques et fonctionnelles m'ont permis de démontrer que l'absence de CD226 conduit à une altération majeure de la prolifération et des fonctions effectrices des LT CD8+ stimulés par le TCR. Mes analyses effectuées sur des LT CD8+ infiltrant la tumeur chez des patients atteints de cancer et chez des souris porteuses de tumeur m'ont conduit à observer que le développement tumoral favorise l'accumulation des LT CD8+ CD226- hyporépondeurs au TCR au site de la tumeur. Des modèles murins précliniques ont pu ensuite mettre en évidence que cette accumulation progressive des LT CD8+ CD226- dépend du facteur de transcription Eomes. Le phénotype " épuisé " est identique entre les LT CD8+ CD226+ et LT CD226- infiltrant la tumeur et seule l'absence de CD226 est à l'origine de la diminution des fonctions effectrices des LT CD8+ CD226-. De façon importante, j'ai pu observer que l'immunothérapie anti-PD-1 ne parvient pas à restaurer les fonctions des LT CD8+ CD226-, contrairement aux LT CD8+ CD226+. Ainsi, mes résultats indiquent qu'au-delà d'exprimer des récepteurs inhibiteurs, la perte du récepteur coactivateur CD226 est un nouveau mécanisme pouvant contribuer à l'épuisement lymphocytaire et à l'échappement de la tumeur aux LT CD8+. CD226 serait donc un marqueur de bon pronostic pour les patients traités avec les immunothérapies anti-PD-1, et inversement l'absence de CD226 pourrait expliquer en partie les faibles réponses cliniques de certains patients.CD8+ cytotoxic T lymphocytes (CTL) are key immune cells that play an important role in the control of tumor development through their ability of killing cancer cells. However, cancer cells can frequently escape CD8 T-cell recognition and cytolytic functions through the engagement of inhibitory receptors such as CTLA-4 and PD-1. Although immune checkpoint blockade (ICB) such as monoclonal antibody (mAb) anti-PD-1 has represented a promising cancer therapy in cancer care, clinical responses are not observed in the majority of cancer patients. Therefore, elucidating the mechanisms of this lack of responsiveness and finding additional signals that regulate CD8+ T cell anti-tumor functions has become a major priority. While most of the experimental strategy mainly focus on the identification of additional inhibitory receptors, the importance of coactivating receptors in the antitumor CD8+ T cell functions and ICB efficacy remains to be better investigated. Initially described as an adhesion molecule, CD226 (DNAM-1) is co-activating receptor expressed by NK cells and CD8+ T cells that stimulate the secretion of pro-inflammatory cytokines and release of cytolytic granules towards target cells. Its ligands, the nectin and nectin-like receptors CD112 and CD155, are often expressed on cancer cells and CD226 was shown to play a critical role in immunosurveillance in numerous tumor mouse models. The inhibitory receptors TIGIT and CD96 that compete with CD226 were recently identified as promising immunotherapeutic targets to restore CD8+ T cell reactivity against cancer, thus highlighting the importance of CD226 axis in the regulation of anti-tumor immune responses. During my PhD, I found that CD226 identifies CD226- CD8+ and CD226+ CD8+ T cells populations in healthy donors and in cancers patients. Through transcriptomic, molecular and functional analysis, I found that the CD226 absence alters CD8+ T cell responsiveness to TCR stimulation. Unlike CD226+ CD8+ T cells, CD226- CD8+ T cells have deeply intrinsic functional abnormalities such as poor proliferation, cytokines production and cytotoxic functions upon TCR stimulation. Using complementary set of experiments involving human samples and mouse tumors models, I observed that tumor development favors the accumulation of tumor-infiltrating CD226- CD8+ T lymphocytes (TILs) through an Eomes-dependent mechanism. In cancer patients and in preclinical models, the similar exhausted phenotype between CD226- and CD226+ CD8+ TILs suggest that the absence of CD226 identifies highly dysfunctional CD8+ T cells. Importantly, I observed that anti-PD-1 immunotherapy failed to restore effector functions of CD226- CD8+ T cells. Therefore, my results strongly suggest that in addition of expressing inhibitory immune checkpoints, cancer could evade CTL-based mechanisms through the downregulation of CD226. The loss of CD226 could represent a novel mechanism of tumor resistance to ICB and partially explain the functional failures of CD8+ T cells responsible for poor clinical responses in a fraction of cancer patients. Therefore, CD226 could be a predictive marker for the clinical outcomes of ICB-treated cancer patients

Polychromatic guide star: feasibility study

International audienceAdaptive optics at astronomical telescopes aims at correcting in real time the phase corrugations of incoming wavefronts caused by the turbulent atmosphere, as early proposed by Babcock. Measuring the phase errors requires a bright source located within the isoplanatic patch of the program source. The probability that such a reference source exists is a function of the wavelength, of the required image quality (Strehl ratio), of the turbulence optical properties, and of the direction of the observation. It turns out that the sky coverage is disastrously low in particular in the visible wavelength range where, unfortunately, the gain in spatial resolution brought by adaptive optics is the largest. Foy and Labeyrie have proposed to overcome this difficulty by creating an artificial point source in the sky in the direction of the observation relying on the backscattered light due to a laser beam. This laser guide star (hereinafter referred to as LGS) can be bright enough to allow us to accurately measure the wavefront phase errors, except for two modes which are the piston (not relevant in this case) and the tilt. Pilkington has emphasized that the round trip time of the laser beam to the mesosphere, where the LGS is most often formed, is significantly shorter than the typical tilt coherence time; then the inverse-return-of-light principle causes deflections of the outgoing and the ingoing beams to cancel. The apparent direction of the LGS is independent of the tilt. Therefore the tilt cannot be measured only from the LGS. Until now, the way to overcome this difficulty has been to use a natural guide star to sense the tilt. Although the tilt is sensed through the entire telescope pupil, one cannot use a faint source because $APEX 90% of the variance of the phase error is in the tilt. Therefore, correcting the tilt requires a higher accuracy of the measurements than for higher orders of the wavefront. Hence current adaptive optics devices coupled with a LGS face low sky coverage. Several methods have been proposed to get a partial sky coverage for the tilt. The only one providing us with a full sky coverage is the polychromatic LGS (hereafter referred to as PLGS). We present here a progress report of the R&D; program Etoile Laser Polychromatique et Optique Adaptative (ELP-OA) carried out in France to develop the PLGS concept. After a short recall of the principles of the PLGS, we will review the goal of ELP-OA and the steps to get over to bring it into play. We finally shortly described the effort in Europe to develop the LGS

Polychromatic guide star: feasibility study

International audienceAdaptive optics at astronomical telescopes aims at correcting in real time the phase corrugations of incoming wavefronts caused by the turbulent atmosphere, as early proposed by Babcock. Measuring the phase errors requires a bright source located within the isoplanatic patch of the program source. The probability that such a reference source exists is a function of the wavelength, of the required image quality (Strehl ratio), of the turbulence optical properties, and of the direction of the observation. It turns out that the sky coverage is disastrously low in particular in the visible wavelength range where, unfortunately, the gain in spatial resolution brought by adaptive optics is the largest. Foy and Labeyrie have proposed to overcome this difficulty by creating an artificial point source in the sky in the direction of the observation relying on the backscattered light due to a laser beam. This laser guide star (hereinafter referred to as LGS) can be bright enough to allow us to accurately measure the wavefront phase errors, except for two modes which are the piston (not relevant in this case) and the tilt. Pilkington has emphasized that the round trip time of the laser beam to the mesosphere, where the LGS is most often formed, is significantly shorter than the typical tilt coherence time; then the inverse-return-of-light principle causes deflections of the outgoing and the ingoing beams to cancel. The apparent direction of the LGS is independent of the tilt. Therefore the tilt cannot be measured only from the LGS. Until now, the way to overcome this difficulty has been to use a natural guide star to sense the tilt. Although the tilt is sensed through the entire telescope pupil, one cannot use a faint source because $APEX 90% of the variance of the phase error is in the tilt. Therefore, correcting the tilt requires a higher accuracy of the measurements than for higher orders of the wavefront. Hence current adaptive optics devices coupled with a LGS face low sky coverage. Several methods have been proposed to get a partial sky coverage for the tilt. The only one providing us with a full sky coverage is the polychromatic LGS (hereafter referred to as PLGS). We present here a progress report of the R&D; program Etoile Laser Polychromatique et Optique Adaptative (ELP-OA) carried out in France to develop the PLGS concept. After a short recall of the principles of the PLGS, we will review the goal of ELP-OA and the steps to get over to bring it into play. We finally shortly described the effort in Europe to develop the LGS

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

L’Inde (sans les Anglais), par Pierre Loti. — Calmann Lévy

Weulersse Georges. L’Inde (sans les Anglais), par Pierre Loti. — Calmann Lévy. In: La revue pédagogique, tome 43, Juillet-Décembre 1903. pp. 201-202