αvβ3-dependent cross-presentation of matrix metalloproteinase–2 by melanoma cells gives rise to a new tumor antigen

A large array of antigens that are recognized by tumor-specific T cells has been identified and shown to be generated through various processes. We describe a new mechanism underlying T cell recognition of melanoma cells, which involves the generation of a major histocompatibility complex class I–restricted epitope after tumor-mediated uptake and processing of an extracellular protein—a process referred to as cross-presentation—which is believed to be restricted to immune cells. We show that melanoma cells cross-present, in an αvβ3-dependent manner, an antigen derived from secreted matrix metalloproteinase–2 (MMP-2) to human leukocyte antigen A*0201-restricted T cells. Because MMP-2 activity is critical for melanoma progression, the MMP-2 peptide should be cross-presented by most progressing melanomas and represents a unique antigen for vaccine therapy of these tumors

Unraveling the Developmental and Genetic Mechanisms Underpinning Floral Architecture in Proteaceae

Proteaceae are a basal eudicot family with a highly conserved floral groundplan but which displays considerable variation in other aspects of floral and inflorescence morphology. Their morphological diversity and phylogenetic position make them good candidates for understanding the evolution of floral architecture, in particular the question of the homology of the undifferentiated perianth with the differentiated perianth of core eudicots, and the mechanisms underlying the repeated evolution of zygomorphy. In this paper, we combine a morphological approach to explore floral ontogenesis and a transcriptomic approach to access the genes involved in floral organ identity and development, focusing on Grevillea juniperina, a species from subfamily Grevilleoideae. We present developmental data for Grevillea juniperina and three additional species that differ in their floral symmetry using stereomicroscopy, SEM and High Resolution X-Ray Computed Tomography. We find that the adnation of stamens to tepals takes place at early developmental stages, and that the establishment of bilateral symmetry coincides with the asymmetrical growth of the single carpel. To set a framework for understanding the genetic basis of floral development in Proteaceae, we generated and annotated de novo a reference leaf/flower transcriptome from Grevillea juniperina. We found Grevillea homologs of all lineages of MADS-box genes involved in floral organ identity. Using Arabidopsis thaliana gene expression data as a reference, we found homologs of other genes involved in floral development in the transcriptome of G. juniperina. We also found at least 21 class I and class II TCP genes, a gene family involved in the regulation of growth processes, including floral symmetry. The expression patterns of a set of floral genes obtained from the transcriptome were characterized during floral development to assess their organ specificity and asymmetry of expression

Folding of Matrix Metalloproteinase-2 Prevents Endogenous Generation of MHC Class-I Restricted Epitope

BACKGROUND: We previously demonstrated that the matrix metalloproteinase-2 (MMP-2) contained an antigenic peptide recognized by a CD8 T cell clone in the HLA-A*0201 context. The presentation of this peptide on class I molecules by human melanoma cells required a cross-presentation mechanism. Surprisingly, the classical endogenous processing pathway did not process this MMP-2 epitope. METHODOLOGY/PRINCIPAL FINDINGS: By PCR directed mutagenesis we showed that disruption of a single disulfide bond induced MMP-2 epitope presentation. By Pulse-Chase experiment, we demonstrated that disulfide bonds stabilized MMP-2 and impeded its degradation. Finally, using drugs, we documented that mutated MMP-2 epitope presentation used the proteasome and retrotranslocation complex. CONCLUSIONS/SIGNIFICANCE: These data appear crucial to us since they established the existence of a new inhibitory mechanism for the generation of a T cell epitope. In spite of MMP-2 classified as a self-antigen, the fact that cross-presentation is the only way to present this MMP-2 epitope underlines the importance to target this type of antigen in immunotherapy protocols

Jotereau F: Suboptimal activation of melanoma infiltrating lymphocytes (TIL) due to low avidity of TCR/MHC-tumor peptide interactions

Coculture of melanoma cells and T cell clones derived from tumor-infiltrating lymphocytes (TIL) generally results in lysis of the antigen-bearing tumor cells but to inefficient proliferation and IL-2 secretion by responder T cells. This suboptimal activation is classically explained by an inability of tumor cells to provide costimulatory signals. Here we analyzed the responses to synthetic peptides of HLA-A2.1-restricted CTL clones specific for melanoma antigens MART-1 and NA17-A. We showed that peptide concentrations ranging from 1 pM to 10 nM efficiently sensitized the peptide transporter-deficient T2 cells to lysis. T2 cells pulsed with melanoma peptides also induced TIL proliferation and detectable secretion of IL-2, IFN-~/and GM-CSF, but only for peptide concentrations 10- to 10,000-fold higher than those required for lysis. Hence this suggests that partial triggering of TIL clones by melanoma cells could be due to expression of appropriate MHC-peptide complexes at subthreshold levels. In support of this, we showed that melanoma cells, unable to trigger IL-2 secretion, developed this ability when incubated with the appropriate peptide. These results indicate that the level of antigens expressed on melanoma tumors critically affects TIL activation status and thus, the efficiency of specific immune reactions mediated by these cells

Hainaut, terre musicale (XVIe-XVIIIe s.)

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Des solutions domotiques « interopérables » au service de la prévention, une trop grande ambition ?

Comment les séniors acceptent-ils les solutions domotiques pour favoriser leur autonomie dans la vie quotidienne ? LEROY MERLIN Source a missionné dans le cadre d’une expérimentation menée par le TASDA une équipe de chercheurs pour analyser cette question.Des solutions domotiques pour l’autonomie des séniors : trois approches de recherche. Cette recherche a été menée dans le cadre d’un programme européen d’ampleur (plus de 50 partenaires dans 9 pays entre 2017 et 2020). Son nom de code ? ACTIVAGE (Internet of Things (IoT) for ageing well). Son but ? Faciliter le développement des solutions connectées pour l’autonomie des séniors et assurer la sécurité des données. C’est dans ce cadre que le TASDA et LEROY MERLIN Source ont défini trois axes pour orienter son analyse. Ils ont mobilisé ensemble plusieurs chercheurs dans des disciplines différentes : Gaël Guilloux pour l’approche design ; Tanguy Dufournet pour l’approche sociologique ; Amandine Porcher et Yannick Fouquet pour le volet psycho-ergonomique. Un projet systémique, technique et complexe mais riche d’enseignements.Acceptabilité des solutions domotiques : cumuler les aides humaines et technologiques. Quand est-ce qu’un sénior accepte une solution domotique dans sa vie ? À partir du moment où il y trouve un intérêt et qu’il peut lui donner un sens personnel. En un mot, qu’il se l’approprie. Dans ce cas, le sens donné par un tiers (un professionnel qui assure un suivi par exemple avec accès à la donnée captée) est secondaire pour lui. Ainsi l’offre numérique de demain, pour les « séniors », pourrait figurer dans les « solutions domotiques usuelles ». En revanche les processus de traitement des données et les usages ne devront pas être standards. Ils devront être adaptés au fur et à mesure de l’évolution des besoins du sénior et de son contexte de vie. En conclusion, l’innovation de demain ne doit pas questionner les matériels mais les processus métiers permettant d’adapter leurs usages.Quelle confiance numérique des séniors vis à vis des solutions domotiques ?La confiance numérique repose en grande partie sur le tiers, garant de l’offre. La confiance envers les NTIC en général est restée importante à la fin du projet malgré les dysfonctionnements rencontrés. Sur le terrain de la recherche et des expérimentations, le relais par des acteurs publics que sont les élus locaux et le Département de l’Isère, a été un point majeur de mobilisation des usagers. À terme, il s’agira donc de bien poser “qui” soutient une offre domotique de ce type, indépendamment des modes de financement.Retravailler les processus métiers : Les processus métiers doivent être travaillés pour l’ensemble des parties prenantes. L’expérimentation française du programme ACTIVAGE a été l’occasion de développer ou d’enrichir des processus métiers pour les intervenants à domicile et les domoticiens. Ces travaux sont considérés comme réellement nouveaux pour ces professionnels, ce qui indique l’importance des changements à conduire si ces approches devaient être généralisées

Using α radiation to boost cancer immunity?

Radioimmunotherapy delivers radiation directly to cancer cells by the mean of a tumor specific vector coupled to a radionuclide. Alpha radionuclides are very potent agents to treat disseminated cancer and metastasis. The demonstration that alpha radiation can also induce immunogenic cell death reinforces the interest of their clinical development.JRC.E.5-Nuclear chemistr

Discrimination of dog palatant solutions using human olfactory receptors

International audienc

A ras-Mutated Peptide Targeted by CTL Infiltrating a Human Melanoma Lesion 1

International audienceAgs derived from commonly mutated oncogenic proteins seem ideally suited as targets for tumor immunotherapy. Nonetheless, only a few mutated epitopes efficiently presented by human tumors have thus far been identified. We describe here an approach to identify such epitopes. This approach involves: 1) identifying tumors expressing a ras mutation and isolating the tumor-infiltrating lymphocytes (TIL); 2) transfecting COS cells to induce expression of unknown mutated peptides in the context of a patient's HLA class I molecules; and 3) screening epitope recognition by using TIL from the tumors expressing a ras mutation. By using this approach, there appeared to be a N-ras mutation (a glutamine-to-arginine exchange at residue 61 (Q61R)), detected in a melanoma lesion, which was recognized specifically by the autologous TIL in the HLA-A*0101 context. The ras peptide 55-64 Q61R was the epitope of these TIL and was regularly presented by Q61R-mutated HLA-A*0101 ؉ melanoma cell lines. This peptide and its wild-type homolog (55-64 wt) bound to HLA-A*0101 with similar affinities. However, only the mutated peptide could induce specific CTL expansion from PBL. All the CTL clones specific to the mutated peptide, failed to recognize the wild-type sequence on both COS and melanoma cells. These data thus show that oncogenic protein mutations can create shared tumor-specific CTL epitopes, efficiently presented by tumor cells, and that screening for oncogene-transfected COS cell recognition by TIL (from tumors containing mutations) is a powerful approach for the identification of these epitopes