Influence of local environmental olfactory cues on place learning in rats

The aim of the present study was to assess the influence of local environmental olfactory cues on place learning in rats. We developed a new experimental design allowing the comparison of the use of local olfactory and visual cues in spatial and discrimination learning. We compared the effect of both types of cues on the discrimination of a single food source in an open-field arena. The goal was either in a fixed or in a variable location, and could be indicated by local olfactory and/or visual cues. The local cues enhanced the discrimination of the goal dish, whether it was in a fixed or in a variable location. However, we did not observe any overshadowing of the spatial information by the local olfactory or visual cue. Rats relied primarily on distant visuospatial information to locate the goal, neglecting local information when it was in conflict with the spatial information.

The in vivo performance of magnetic particle-loaded injectable, in situ gelling, carriers for the delivery of local hyperthermia.

We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxide nanoparticles (SPIONs) as a form of minimally invasive treatment of cancer lesions by magnetically induced local hyperthermia. We developed injectable formulations that form gels entrapping magnetic particles into a tumor. We used SPIONs embedded in silica microparticles to favor syringeability and incorporated the highest proportion possible to allow large heating capacities. Hydrogel, single-solvent organogel and cosolvent (low-toxicity hydrophilic solvent) organogel formulations were injected into human cancer tumors xenografted in mice. The thermoreversible hydrogels (poloxamer, chitosan), which accommodated 20% w/v of the magnetic microparticles, proved to be inadequate. Alginate hydrogels, however, incorporated 10% w/v of the magnetic microparticles, and the external gelation led to strong implants localizing to the tumor periphery, whereas internal gelation failed in situ. The organogel formulations, which consisted of precipitating polymers dissolved in single organic solvents, displayed various microstructures. A 8% poly(ethylene-vinyl alcohol) in DMSO containing 40% w/v of magnetic microparticles formed the most suitable implants in terms of tumor casting and heat delivery. Importantly, it is of great clinical interest to develop cosolvent formulations with up to 20% w/v of magnetic microparticles that show reduced toxicity and centered tumor implantation.

Preliminary Experience in Treatment of Papillary and Macular Retinoblastoma: Evaluation of Local Control and Local Complications After Treatment with Linear Accelerator-Based Stereotactic Radiotherapy with Micromultileaf Collimator as Second-Line or Salvage Treatment after chemotherapy.

PURPOSE: To determine the local control and complication rates for children with papillary and/or macular retinoblastoma progressing after chemotherapy and undergoing stereotactic radiotherapy (SRT) with a micromultileaf collimator. METHODS AND MATERIALS: Between 2004 and 2008, 11 children (15 eyes) with macular and/or papillary retinoblastoma were treated with SRT. The mean age was 19 months (range, 2-111). Of the 15 eyes, 7, 6, and 2 were classified as International Classification of Intraocular Retinoblastoma Group B, C, and E, respectively. The delivered dose of SRT was 50.4 Gy in 28 fractions using a dedicated micromultileaf collimator linear accelerator. RESULTS: The median follow-up was 20 months (range, 13-39). Local control was achieved in 13 eyes (87%). The actuarial 1- and 2-year local control rates were both 82%. SRT was well tolerated. Late adverse events were reported in 4 patients. Of the 4 patients, 2 had developed focal microangiopathy 20 months after SRT; 1 had developed a transient recurrence of retinal detachment; and 1 had developed bilateral cataracts. No optic neuropathy was observed. CONCLUSIONS: Linear accelerator-based SRT for papillary and/or macular retinoblastoma in children resulted in excellent tumor control rates with acceptable toxicity. Additional research regarding SRT and its intrinsic organ-at-risk sparing capability is justified in the framework of prospective trials.

Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance.

Although tumor-specific CD8 T-cell responses often develop in cancer patients, they rarely result in tumor eradication. We aimed at studying directly the functional efficacy of tumor-specific CD8 T cells at the site of immune attack. Tumor lesions in lymphoid and nonlymphoid tissues (metastatic lymph nodes and soft tissue/visceral metastases, respectively) were collected from stage III/IV melanoma patients and investigated for the presence and function of CD8 T cells specific for the tumor differentiation antigen Melan-A/MART-1. Comparative analysis was conducted with peripheral blood T cells. We provide evidence that in vivo-priming selects, within the available naive Melan-A/MART-1-specific CD8 T-cell repertoire, cells with high T-cell receptor avidity that can efficiently kill melanoma cells in vitro. In vivo, primed Melan-A/MART-1-specific CD8 T cells accumulate at high frequency in both lymphoid and nonlymphoid tumor lesions. Unexpectedly, however, whereas primed Melan-A/MART-1-specific CD8 T cells that circulate in the blood display robust inflammatory and cytotoxic functions, those that reside in tumor lesions (particularly in metastatic lymph nodes) are functionally tolerant. We show that both the lymph node and the tumor environments blunt T-cell effector functions and offer a rationale for the failure of tumor-specific responses to effectively counter tumor progression.

Effective exposure to solar UV in building workers: influence of local and individual factors.

Excessive exposure to solar UV light is the main cause of skin cancers in humans. UV exposure depends on environmental as well as individual factors related to activity. Although outdoor occupational activities contribute significantly to the individual dose received, data on effective exposure are scarce and limited to a few occupations. A study was undertaken in order to assess effective short-term exposure among building workers and characterize the influence of individual and local factors on exposure. The effective exposure of construction workers in a mountainous area in the southern part of Switzerland was investigated through short-term dosimetry (97 dosimeters). Three altitudes, of about 500, 1500 and 2500 m were considered. Individual measurements over 20 working periods were performed using Spore film dosimeters on five body locations. The postural activity of workers was concomitantly recorded and static UV measurements were also performed. Effective exposure among building workers was high and exceeded occupational recommendations, for all individuals for at least one body location. The mean daily UV dose in plain was 11.9 SED (0.0-31.3 SED), in middle mountain 21.4 SED (6.6-46.8 SED) and in high mountain 28.6 SED (0.0-91.1 SED). Measured doses between workers and anatomical locations exhibited a high variability, stressing the role of local exposure conditions and individual factors. Short-term effective exposure ranged between 0 and 200% of ambient irradiation, indicating the occurrence of intense, subacute exposures. A predictive irradiation model was developed to investigate the role of individual factors. Posture and orientation were found to account for at least 38% of the total variance of relative individual exposure, and were also found to account more than altitude on the total variance of effective daily exposures. Targeted sensitization actions through professional information channels and specific prevention messages are recommended. Altitude outdoor workers should also benefit from preventive medical examination.

Similar patterns of local barn owl adaptation in the Middle East and Europe with respect to melanic coloration

The maintenance of phenotypic variation is a central question in evolutionary biology. A commonly suggested mechanism is that of local adaptation, whereby different phenotypes are adapted to alternative environmental conditions. A recent study in the European barn owl (Tyto alba) has shown that natural selection maintains a strong clinal variation in reddish pheomelanin-based coloration. Studies in the region where phenotypic variation in this owl is the highest in Europe have further demonstrated that dark-reddish and pale-reddish owls exploit open and wooded habitats, predate voles and wood mice, and are long-tailed and short-tailed, respectively. However, it remains unclear as to whether these traits evolved as a consequence of allopatric evolution of dark colour in northern Europe and white colour in southern Europe, during which owls could have also evolved different morphologies and foraging behaviour. This scenario implies that covariation between coloration and foraging behaviour could be a specificity of the European continent, which is not found in other worldwide-distributed populations. To investigate this issue we studied a barn owl population in the Middle East. Our results show that, as in Central Europe, dark-reddish female owls breed more often in the open landscape than their pale-reddish female conspecifics, their offspring are fed with more voles than Muridae, and they are longer-winged and longer-tailed. These findings indicate that in the barn owl the association in females between pheomelanin-based coloration and foraging behaviour and morphology is not restricted to the European continent but may well evolve in sympatry in many barn owl populations worldwide.

Extracapsular tumor spread and the risk of local, axillary and supraclavicular recurrence in node-positive, premenopausal patients with breast cancer.

BACKGROUND: Extracapsular tumor spread (ECS) has been identified as a possible risk factor for breast cancer recurrence, but controversy exists regarding its role in decision making for regional radiotherapy. This study evaluates ECS as a predictor of local, axillary, and supraclavicular recurrence. PATIENTS AND METHODS: International Breast Cancer Study Group Trial VI accrued 1475 eligible pre- and perimenopausal women with node-positive breast cancer who were randomly assigned to receive three to nine courses of classical combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. ECS status was determined retrospectively in 933 patients based on review of pathology reports. Cumulative incidence and hazard ratios (HRs) were estimated using methods for competing risks analysis. Adjustment factors included treatment group and baseline patient and tumor characteristics. The median follow-up was 14 years. RESULTS: In univariable analysis, ECS was significantly associated with supraclavicular recurrence (HR = 1.96; 95% confidence interval 1.23-3.13; P = 0.005). HRs for local and axillary recurrence were 1.38 (P = 0.06) and 1.81 (P = 0.11), respectively. Following adjustment for number of lymph node metastases and other baseline prognostic factors, ECS was not significantly associated with any of the three recurrence types studied. CONCLUSIONS: Our results indicate that the decision for additional regional radiotherapy should not be based solely on the presence of ECS.

Proximal tibia volumetric bone mineral density is correlated to the magnitude of local acceleration in male long distance runners.

Introduction: The beneficial effect of physical exercise on bone mineral density (BMD) is at least partly explained by the forces exerted directly on the bones. Male runners present generally higher BMD than sedentary individuals. We postulated that the proximal tibia BMD is related to the running distance as well as to the magnitude of the shocks (while running) in male runners. Methods: A prospective study (three yearly measurements) included 81 healthy male subjects: 16 sedentary lean subjects and three groups of runners (5-30 km/week, n=19; 30-50 km/week, n=29; 50-100 km/week, n=17). Several measurements were performed at the proximal tibia level: volumetric BMD (vBMD), cortical index (CI) i.e. an index of cortical bone thickness and peak accelerations (an index of shocks during heel strike) while running (measured by a 3-D accelerometer). A general linear model assessed the prediction of vBMD or CI by a) simple effects (running distance, peak accelerations, time) and b) interactions (for instance if vBMD prediction by peak acceleration depends on running distance). Results: CI and vBMD a) increase with running distance to reach a plateau over 30 km/wk, b) are positively associated with peak accelerations over 30 km/week. Discussion: Running may be associated with high peak accelerations in order to have beneficial effects on BMD. More important strains are needed to be associated with the same increase in BMD during running sessions of short duration than those of long duration. Conclusion: CI and vBMD are associated with the magnitude of the shocks during heel strike in runners. Key words: Bone mineral density, strains, physical exercise, running distance.

Effect of low-dose chest irradiation before chemotherapy on the rate of local failure in small-cell lung cancer.

PURPOSE: To evaluate the rate of tumor recurrence within the irradiated volume after initial low-dose irradiation of limited-stage small-cell lung cancer (SCLC), to assess the tolerance of a sequential combination of low-dose chest irradiation followed by chemotherapy, and to confirm the responsiveness of limited-stage SCLC to low-dose irradiation. METHODS AND MATERIALS: In this pilot study, 26 patients with limited-stage SCLC were treated by first-line 20-Gy thoracic irradiation followed 3 weeks later by chemotherapy (cisplatin, doxorubicin, and etoposide for six cycles). RESULTS: We present our final results with a median follow-up of surviving patients of 7 years. The response rate to this low-dose irradiation was 83%, with an overall response rate to radiochemotherapy of 96% and a median survival of 21 months. No unexpected early or late toxicity was observed. The rate of initial isolated local failure was 8%, which compares favorably with other published series using higher doses of radiochemotherapy. CONCLUSION: An initial chest irradiation of 20 Gy before chemotherapy could be sufficient to reduce the risk of local failure during the time of survival of patients with limited-stage SCLC. Potential advantages of this treatment may be the prevention of resistance mechanisms to radiotherapy induced by preliminary chemotherapy and a reduced radiation-induced toxicity.

Integration of local-scale hydrological and regional-scale geophysical based on a nonlinear Bayesian sequential simulation approach

Significant progress has been made with regard to the quantitative integration of geophysical and hydrological data at the local scale. However, extending the corresponding approaches to the regional scale represents a major, and as-of-yet largely unresolved, challenge. To address this problem, we have developed a downscaling procedure based on a non-linear Bayesian sequential simulation approach. The basic objective of this algorithm is to estimate the value of the sparsely sampled hydraulic conductivity at non-sampled locations based on its relation to the electrical conductivity, which is available throughout the model space. The in situ relationship between the hydraulic and electrical conductivities is described through a non-parametric multivariate kernel density function. This method is then applied to the stochastic integration of low-resolution, re- gional-scale electrical resistivity tomography (ERT) data in combination with high-resolution, local-scale downhole measurements of the hydraulic and electrical conductivities. Finally, the overall viability of this downscaling approach is tested and verified by performing and comparing flow and transport simulation through the original and the downscaled hydraulic conductivity fields. Our results indicate that the proposed procedure does indeed allow for obtaining remarkably faithful estimates of the regional-scale hydraulic conductivity structure and correspondingly reliable predictions of the transport characteristics over relatively long distances.

Dissection of local and systemic transcriptional responses to phosphate starvation in Arabidopsis.

Phosphate is a crucial and often limiting nutrient for plant growth. To obtain inorganic phosphate (P(i) ), which is very insoluble, and is heterogeneously distributed in the soil, plants have evolved a complex network of morphological and biochemical processes. These processes are controlled by a regulatory system triggered by P(i) concentration, not only present in the medium (external P(i) ), but also inside plant cells (internal P(i) ). A 'split-root' assay was performed to mimic a heterogeneous environment, after which a transcriptomic analysis identified groups of genes either locally or systemically regulated by P(i) starvation at the transcriptional level. These groups revealed coordinated regulations for various functions associated with P(i) starvation (including P(i) uptake, P(i) recovery, lipid metabolism, and metal uptake), and distinct roles for members in gene families. Genetic tools and physiological analyses revealed that genes that are locally regulated appear to be modulated mostly by root development independently of the internal P(i) content. By contrast, internal P(i) was essential to promote the activation of systemic regulation. Reducing the flow of P(i) had no effect on the systemic response, suggesting that a secondary signal, independent of P(i) , could be involved in the response. Furthermore, our results display a direct role for the transcription factor PHR1, as genes systemically controlled by low P(i) have promoters enriched with P1BS motif (PHR1-binding sequences). These data detail various regulatory systems regarding P(i) starvation responses (systemic versus local, and internal versus external P(i) ), and provide tools to analyze and classify the effects of P(i) starvation on plant physiology.

Characterization of local and systemic immune-modulation in melanoma patients

Le mélanome cutané est un des cancers les plus agressifs et dont l'incidence augmente le plus en Suisse. Une fois métastatique, le pronostic de survie moyenne avec les thérapies actuelles est d'environ huit mois, avec moins de 5% de survie à cinq ans. Les récents progrès effectués dans la compréhension de la biologie de la cellule tumorale mais surtout dans l'importance du système immunitaire dans le contrôle de ce cancer ont permis le développement de nouveaux traitements novateurs et prometteurs. Ces thérapies, appelées immunothérapies, reposent sur la stimulation et l'augmentation de la réponse immunitaire à la tumeur. Alors que les derniers essais cliniques ont démontré l'efficacité de ces traitements chez les patients avec des stades avancés de la maladie, le contrôle de la maladie à long- terme est seulement atteint chez une minorité des patients. La suppression locale et systémique de la réponse immunitaire spécifique anti-tumorale apparaitrait comme une des raisons expliquant la persistance d'un mauvais pronostic clinique chez ces patients. Des études sur les souris ont montré que les vaisseaux lymphatiques joueraient un rôle primordial dans ce processus en induisant une tolérance immune, ce qui permettrait à la tumeur d'échapper au contrôle du système immunitaire et métastatiser plus facilement. Ces excitantes découvertes n'ont pas encore été établi et prouvé chez l'homme. Dans cette thèse, nous montrons pour la première fois que les vaisseaux lymphatiques sont directement impliqués dans la modulation de la réponse immunitaire au niveau local et systémique dans le mélanome chez l'homme. Ces récentes découvertes montrent le potentiel de combiner des thérapies visant le système lymphatique avec les immunothérapies actuellement utilisées afin d'améliorer le pronostic des patients atteint du mélanome. -- Cutaneous melanoma is one of the most invasive and metastatic human cancers and causes 75% of skin cancer mortality. Current therapies such as surgery and chemotherapy fail to control metastatic disease, and relapse occurs frequently due to microscopic residual lesions. It is, thus, essential to develop and optimize novel therapeutic strategies to improve curative responses in these patients. In recent decades, tumor immunologists have revealed the development of spontaneous adaptive immune responses in melanoma patients, leading to the accumulation of highly differentiated tumor-specific T cells at the tumor site. This remains one of the most powerful prognostic markers to date. Immunotherapies that augment the natural function of these tumor-specific T cells have since emerged as highly attractive therapeutic approaches to eliminate melanoma cells. While recent clinical trials have demonstrated great progress in the treatment of advanced stage melanoma, long-term disease control is still only achieved in a minority of patients. Local and systemic immune suppression by the tumor appears to be responsible, in part, for this poor clinical evolution. These facts underscore the need for a better analysis and characterization of immune- related pathways within the tumor microenvironment (TME), as well as at the systemic level. The overall goal of this thesis is, thus, to obtain greater insight into the complexity and heterogeneity of the TME in human melanoma, as well as to investigate immune modulation beyond the TME, which ultimately influences the immune system throughout the whole body. To achieve this, we established two main objectives: to precisely characterize local and systemic immune modulation (i) in untreated melanoma patients and (ii) in patients undergoing peptide vaccination or checkpoint blockade therapy with anti-cytotoxic T- lymphocyte-asisctaed protein-4 (CTLA-4) antibody. In the first and main part of this thesis, we analyzed lymphatic vessels in relation to anti-tumor immune responses in tissues from vaccinated patients using a combination of immunohistochemistry (IHC) techniques, whole slide scanning/analysis, and an automatic quantification system. Strikingly, we found that increased lymphatic vessel density was associated with high expression of immune suppressive molecules, low functionality of tumor-infiltrating CD8+ T cells and decreased cytokine production by tumor-antigen specific CD8+ T cells in the blood. These data revealed a previously unappreciated local and systemic role of lymphangiogenesis in modulating T cell responses in human cancer and support the use of therapies that target lymphatic vessels combined with existing and future T cell based therapies. In the second objective, we describe a metastatic melanoma patient who developed pulmonary sarcoid-like granulomatosis following repetitive vaccination with peptides and CpG. We demonstrated that the onset of this pulmonary autoimmune adverse event was related to the development of a strong and long-lasting tumor-specific CD8+ T cell response. This constitutes the first demonstration that a new generation tumor vaccine can induce the development of autoimmune adverse events. In the third objective, we assessed the use of Fourier Transform Infrared (FTIR) imaging to identify melanoma cells and lymphocyte subpopulations in lymph node (LN) metastasis tissues, thanks to a fruitful collaboration with researchers in Brussels. We demonstrated that the different cell types in metastatic LNs have different infrared spectral features allowing automated identification of these cells. This technic is therefore capable of distinguishing known and novel biological features in human tissues and has, therefore, significant potential as a tool for histopathological diagnosis and biomarker assessment. Finally, in the fourth objective, we investigated the role of colony- stimulating factor-1 (CSF-1) in modulating the anti-tumor response in ipilimumab-treated patients using IHC and in vitro co-cultures, revealing that melanoma cells produce CSF-1 via CTL-derived cytokines when attacked by cytotoxic T lymphocytes (CTLs), resulting in the recruitment of immunosuppressive monocytes. These findings support the combined use of CSF-1R blockade with T cell based immunotherapy for melanoma patients. Taken together, our results reveal the existence of novel mechanisms of immune modulation and thus promote the optimization of combination immunotherapies against melanoma. -- Le mélanome cutané est un des cancers humains les plus invasifs et métastatiques et est responsable de 75% de la mortalité liée aux cancers de la peau. Les thérapies comme la chirurgie et la chimiothérapie ont échoué à contrôler le mélanome métastatique, par ailleurs les rechutes sous ces traitements ont été montrées fréquentes. Il est donc essentiel de développer et d'optimiser de nouvelles stratégies thérapeutiques pour améliorer les réponses thérapeutiques de ces patients. Durant les dernières décennies, les immunologistes spécialisés dans les tumeurs ont démontré qu'un patient atteint du mélanome pouvait développer spontanément une réponse immune adaptative à sa tumeur et que l'accumulation de cellules T spécifiques tumorales au sein même de la tumeur était un des plus puissants facteurs pronostiques. Les immunothérapies qui ont pour but d'augmenter les fonctions naturelles de ces cellules T spécifiques tumorales ont donc émergé comme des approches thérapeutiques très attractives pour éliminer les cellules du mélanome. Alors que les derniers essais cliniques ont démontré un progrès important dans le traitement des formes avancées du mélanome, le contrôle de la maladie à long-terme est seulement atteint chez une minorité des patients. La suppression immune locale et systémique apparaitrait comme une des raisons expliquant la persistance d'un mauvais pronostic clinique chez ces patients. Ces considérations soulignent la nécessité de mieux analyser et caractériser les voies immunitaires non seulement au niveau local dans le microenvironement tumoral mais aussi au niveau systémique dans le sang des patients. Le but de cette thèse est d'obtenir une plus grande connaissance de la complexité et de l'hétérogénéité du microenvironement tumoral dans les mélanomes mais aussi d'investiguer la modulation immunitaire au delà du microenvironement tumoral au niveau systémique. Afin d'atteindre ce but, nous avons établi deux objectifs principaux : caractériser précisément la modulation locale et systémique du système immunitaire (i) chez les patients atteints du mélanome qui n'ont pas reçu de traitement et (ii) chez les patients qui ont été traités soit par des vaccins soit par des thérapies qui bloquent les points de contrôles. Dans la première et majeure partie de cette thèse, nous avons analysé les vaisseaux lymphatiques en relation avec la réponse immunitaire anti-tumorale dans les tissus des patients vaccinés grâce à des techniques d'immunohistochimie et de quantification informatisé et automatique des marquages. Nous avons trouvé qu'une densité élevée de vaisseaux lymphatiques dans la tumeur était associée à une plus grande expression de molécules immunosuppressives ainsi qu'à une diminution de la fonctionnalité des cellules T spécifiques tumoral dans la tumeur et dans le sang des patients. Ces résultats révèlent un rôle jusqu'à là inconnu des vaisseaux lymphatiques dans la modulation directe du système immunitaire au niveau local et systémique dans les cancers de l'homme. Cette recherche apporte finalement des preuves du potentiel de combiner des thérapies visant le système lymphatique avec des autres immunothérapies déjà utilisées en clinique. Dans le second objectif, nous rapportons le cas d'un patient atteint d'un mélanome avec de multiples métastases qui a développé à la suite de plusieurs vaccinations répétées et consécutives avec des peptides et du CpG, un évènement indésirable sous la forme d'une granulomatose pulmonaire sarcoid-like. Nous avons démontré que l'apparition de cet évènement était intimement liée au développement d'une réponse immunitaire durable et spécifique contre les antigènes de la tumeur. Par là- même, nous prouvons pour la première fois que la nouvelle génération de vaccins est aussi capable d'induire des effets indésirables auto-immuns. Pour le troisième objectif, nous avons voulu savoir si l'utilisation de la spectroscopie infrarouge à transformée de Fourier (IRTF) était capable d'identifier les cellules du mélanome ainsi que les différents sous-types cellulaires dans les ganglions métastatiques. Grâce à nos collaborateurs de Bruxelles, nous avons pu établir que les diverses composantes cellulaires des ganglions atteints par des métastases du mélanome présentaient des spectres infrarouges différents et qu'elles pouvaient être identifiées d'une façon automatique. Cette nouvelle technique permettrait donc de distinguer des caractéristiques biologiques connues ou nouvelles dans les tissus humains qui auraient des retombées pratiques importantes dans le diagnostic histopathologique et dans l'évaluation des biomarqueurs. Finalement dans le dernier objectif, nous avons investigué le rôle du facteur de stimulation des colonies (CSF-1) dans la modulation de la réponse immunitaire anti-tumorale chez les patients qui ont été traités par l'Ipilimumab. Nos expériences in vivo au niveau des tissus tumoraux et nos co-cultures in vitro nous ont permis de démontrer que les cytokines secrétées par les cellules T spécifiques anti-tumorales induisaient la sécrétion de CSF-1 dans les cellules du mélanome ce qui résultait en un recrutement de monocytes immunosuppresseurs. Dans son ensemble, cette thèse révèle donc l'existence de nouveaux mécanismes de modulation de la réponse immunitaire anti-tumorale et propose de nouvelles optimisations de combinaison d'immunothérapies contre le mélanome.