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Tumours often evade CD8 T-cell immunity by downregulating TAP. T-cell epitopes associated with impaired peptide processing are immunogenic non-mutated neoantigens that emerge during tumour immune evasion. The preprocalcitonin (ppCT)16–25 neoepitope belongs to this category of antigens. Here we show that most human lung tumours display altered expression of TAP and frequently express ppCT self-antigen. We also show that ppCT includes HLA-A2-restricted epitopes that are processed by TAP-independent and -dependent pathways. Processing occurs in either the endoplasmic reticulum, by signal peptidase and signal peptide peptidase, or in the cytosol after release of a signal peptide precursor or retrotranslocation of a procalcitonin substrate by endoplasmic-reticulum-associated degradation. Remarkably, ppCT peptide-based immunotherapy induces efficient T-cell responses toward antigen processing and presenting machinery-impaired tumours transplanted into HLA-A*0201-transgenic mice and in NOD-scid-Il2rγnull mice adoptively transferred with human PBMC. Thus, ppCT-specific T lymphocytes are promising effectors for treatment of tumours that have escaped immune recognition., Tumours can escape CD8 T-cell immunity by down-regulating antigen presentation machinery components, such as TAP. Here the authors describe tumour antigenic peptides processed by TAP-independent and -dependent pathways and show in mouse models that these peptides can be exploited to induce antitumor T-cell activity when TAP expression is downregulated.

Recent advances in cancer treatment have emerged from new immunotherapies targeting T-cell inhibitory receptors, including cytotoxic T-lymphocyte associated antigen (CTLA)-4 and programmed cell death (PD)-1. In this context, anti-CTLA-4 and anti-PD-1 monoclonal antibodies have demonstrated survival benefits in numerous cancers, including melanoma and non-small-cell lung carcinoma. PD-1-expressing CD8+ T lymphocytes appear to play a major role in the response to these immune checkpoint inhibitors (ICI). Cytotoxic T lymphocytes (CTL) eliminate malignant cells through recognition by the T-cell receptor (TCR) of specific antigenic peptides presented on the surface of cancer cells by major histocompatibility complex class I/beta-2-microglobulin complexes, and through killing of target cells, mainly by releasing the content of secretory lysosomes containing perforin and granzyme B. T-cell adhesion molecules and, in particular, lymphocyte-function-associated antigen-1 and CD103 integrins, and their cognate ligands, respectively, intercellular adhesion molecule 1 and E-cadherin, on target cells, are involved in strengthening the interaction between CTL and tumor cells. Tumor-specific CTL have been isolated from tumor-infiltrating lymphocytes and peripheral blood lymphocytes (PBL) of patients with varied cancers. TCRβ-chain gene usage indicated that CTL identified in vitro selectively expanded in vivo at the tumor site compared to autologous PBL. Moreover, functional studies indicated that these CTL mediate human leukocyte antigen class I-restricted cytotoxic activity toward autologous tumor cells. Several of them recognize truly tumor-specific antigens encoded by mutated genes, also known as neoantigens, which likely play a key role in antitumor CD8 T-cell immunity. Accordingly, it has been shown that the presence of T lymphocytes directed toward tumor neoantigens is associated with patient response to immunotherapies, including ICI, adoptive cell transfer, and dendritic cell-based vaccines. These tumor-specific mutation-derived antigens open up new perspectives for development of effective second-generation therapeutic cancer vaccines.

Recent advances in cancer treatment have emerged from new immunotherapies targeting T-cell inhibitory receptors, including cytotoxic T-lymphocyte associated antigen (CTLA)-4 and programmed cell death (PD)-1. In this context, anti-CTLA-4 and anti-PD-1 monoclonal antibodies have demonstrated survival benefits in numerous cancers, including melanoma and non-small-cell lung carcinoma. PD-1-expressing CD8+ T lymphocytes appear to play a major role in the response to these immune checkpoint inhibitors (ICI). Cytotoxic T lymphocytes (CTL) eliminate malignant cells through recognition by the T-cell receptor (TCR) of specific antigenic peptides presented on the surface of cancer cells by major histocompatibility complex class I/beta-2-microglobulin complexes, and through killing of target cells, mainly by releasing the content of secretory lysosomes containing perforin and granzyme B. T-cell adhesion molecules and, in particular, lymphocyte-function-associated antigen-1 and CD103 integrins, and their cognate ligands, respectively, intercellular adhesion molecule 1 and E-cadherin, on target cells, are involved in strengthening the interaction between CTL and tumor cells. Tumor-specific CTL have been isolated from tumor-infiltrating lymphocytes and peripheral blood lymphocytes (PBL) of patients with varied cancers. TCRβ-chain gene usage indicated that CTL identified in vitro selectively expanded in vivo at the tumor site compared to autologous PBL. Moreover, functional studies indicated that these CTL mediate human leukocyte antigen class I-restricted cytotoxic activity toward autologous tumor cells. Several of them recognize truly tumor-specific antigens encoded by mutated genes, also known as neoantigens, which likely play a key role in antitumor CD8 T-cell immunity. Accordingly, it has been shown that the presence of T lymphocytes directed toward tumor neoantigens is associated with patient response to immunotherapies, including ICI, adoptive cell transfer, and dendritic cell-based vaccines. These tumor-specific mutation-derived antigens open up new perspectives for development of effective second-generation therapeutic cancer vaccines.

We had previously demonstrated the role of CD103 integrin on lung tumor-infiltrating lymphocyte (TIL) clones in promoting specific TCR-mediated epithelial tumor cell cytotoxicity. However, the contribution of CD103 on intratumoral T cell distribution and functions and the prognosis significance of TIL subpopulations in non–small cell lung carcinoma (NSCLC) have thus far not been systematically addressed. In this study, we show that an enhanced CD103+ TIL subset correlates with improved early stage NSCLC patient survival and increased intraepithelial lymphocyte infiltration. Moreover, our results indicate that CD8+CD103+ TIL, freshly isolated from NSCLC specimens, display transcriptomic and phenotypic signatures characteristic of tissue-resident memory T cells and frequently express PD-1 and Tim-3 checkpoint receptors. This TIL subset also displays increased activation-induced cell death and mediates specific cytolytic activity toward autologous tumor cells upon blockade of the PD-1–PD-L1 interaction. These findings emphasize the role of CD8+CD103+ tissue-resident memory T cells in promoting intratumoral CTL responses and support the rationale for using anti–PD-1 blocking Ab to reverse tumor-induced T cell exhaustion in NSCLC patients.

Introduction et but de l’etude En France, l’obesite emerge comme un probleme de sante majeur. En 2012, plus de 15 % de la population adulte est consideree comme obese, l’OMS met en garde contre une « epidemie » d’ici 2030. La chirurgie bariatrique s’impose progressivement comme l’operation de derniere chance, pour les patients dont les autres tentatives de prise en charge ont successivement echouees. Un des objectifs de l’accompagnement dietetique en chirurgie bariatrique est la preparation a l’intervention et la realimentation la plus precoce possible. Les patients reprennent une alimentation quelques heures apres la chirurgie, rentrent en moyenne au domicile 24 h apres l’intervention. Notre service accompagne les patients en education therapeutique perioperatoire. En preoperatoire, ils sont informes du protocole de realimentation (fractionnement, textures, aliments conseilles/deconseilles…). Le retour postoperatoire se fait en moyenne a j + 15 ce qui nous permet d’identifier les difficultes liees a la realimentation. Nous n’evoquerons donc pas les douleurs peri-operatoires immediates ni celles liees directement a l’obesite. Materiel et methodes Quatre-vingt-quatre dossiers de patients operes depuis janvier 2017 ont ete analyses (73 femmes et 11 hommes de 42 ans d’âge moyen ; 61 Bypass, 10 Sleeve, 5 Bipartitions du transit, 8 Derivations bilio-pancretiques). Nous avons exclu les patients ayant beneficie d’une reprise chirurgicale. L’analyse s’est portee sur les difficultes ponctuelles ou continues rencontrees par les patients. Resultats et analyse statistique Quarante-cinq pour cent des patient interroges n’ont aucunes difficultes, 12 % des reflux gastro œsophagien, 11 % des troubles du transit, 10 % des nausees/vomissement, 7 % une dyspepsie, 7 % une sensation de plenitude jusqu’a la gene, 6 % des douleurs lors de la deglutition, et 2 % un dumping syndrome. Suite a l’identification de ces troubles recurrents, nous avons mis en place des conseils sur les comportements a adopter ou eviter pour limiter ces difficultes (Tableau 1). Enfin des ateliers d’education therapeutique ont ete constitues pour repondre specifiquement aux besoins des patients (fractionnement, transit, stress alimentaire…). Conclusion L’accompagnement doit permettre au patient d’etre acteur de son parcours. La prise en charge rapide en postoperatoire, objective et identifie les difficultes potentielles. Les conseils precoces d’une gestion dietetique et psychologique adaptes concourent a eviter la deterioration de la qualite de vie et de l’apparition d’une symptomatologie digestive.

The morpho-technological study of ceramic is one of the way of defining a chrono-cultural region. Thanks to morphological and technological methods (petrography, radiography…), a study of a large scale has been conducted on the ceramic of Bobigny. The analysis of this significant set gave the opportunity to get a new view on the potery production of the central area of the Ile-de-France, during the second Iron Age. It underlines such socio-culturals practices.

Pourquoi les archéologues scrutent-ils avec autant d'attention les objets qu'ils ont mis au jour, pourquoi les décrivent-ils, les classent-ils, les analysent-ils ? Pourquoi s'efforcent-ils de les situer toujours plus précisément dans le temps et dans l'espace? Est-ce pour le simple plaisir de dresser l'inventaire de toutes les productions humaines du passé dans leur infinie diversité? Non, bien sûr. Leur but, avoué ou non, est de forcer ces témoins muets à nous dire quelque chose sur les communautés humaines qui les ont produits, utilisés, échangés et finalement abandonnés dans leurs maisons ou enfouis dans leurs tombeaux. Quelque chose qui va des connaissances techniques nécessaires pour élaborer un objet jusqu'à la signification symbolique dont celui-ci est investi par la communauté qui l'a créé. Les archéologues font ainsi le pari qu'en ordonnant la diversité des productions matérielles à travers une aire géographique donnée, on peut parvenir à cerner les espaces culturels liés aux divers groupes humains qui s'y sont côtoyés. Pari relevé par douze jeunes doctorants qui s'essaient à l'exercice dans ces pages rassemblant les actes de la première journée doctorale d'archéologie de l'université Paris 1 Panthéon-Sorbonne. Travaillant dans des régions du monde et sur des périodes très diverses – des grottes paléolithiques de Dordogne aux kofun protohistoriques du Japon en passant par les tombes préclassiques du Mexique, les épaves médiévales du Portugal et les icônes byzantines de Chypre –, ils utilisent tous la panoplie des méthodes archéologiques acquises au long de leur formation. Reflet de la diversité des recherches menées au sein de l'École doctorale Archéologie, ce volume inaugure une série au rythme de publication annuel, dont chaque livraison s'articulera autour d'un thème différent.

The observation that depletion or inhibition of regulatory T cells (Tregs) unleashes efficient antitumor effector immune responses that can lead to tumor eradication in mice has opened new perspectives for the development of cancer immunotherapy. The quality and overall efficiency of the effector immune responses induced in the absence of Tregs seem to depend on multiple factors that determine the result of a battle involving effector T cells (Teffs), Tregs and tumor cells. In this study, we investigated the quality of tumor-associated antigens (TAAs) as one such factor. We show that the presence of a strong dominant antigen is required for the induction of effector responses capable of tumor eradication in the absence of Tregs. The sole addition of a dominant antigen on tumor cells does not change tumor growth in unmanipulated mice, but improves tumor eradication rate from a few to almost 100% in the absence of Tregs. This eradication can be shown to result from the recruitment and activation of specific Teffs recognizing this antigen. We also show that the presence of such dominant antigens has the side effect of restricting the breadth of the immune response to other TAAs, which could favor the generation of escape mutant by tumor editing. Taken together, our results highlight the potential, and some requirements for cancer immunotherapy based on Treg depletion. They also show that, ultimately, tumor fate depends on multiple factors that should all be taken into consideration for the design of more efficient immunotherapy.

We identified that the antigen preprocalcitonin (ppCT) is recognized on a human lung carcinoma by a cytotoxic T lymphocyte clone derived from autologous tumor-infiltrating lymphocytes. The antigenic peptide ppCT(16-25) is encoded by the gene calcitonin-related polypeptide alpha (CALCA), which codes for CT and is overexpressed in several lung carcinomas compared with normal tissues. The ppCT peptide is derived from the C-terminal region of the signal peptide and is processed independently of proteasomes and the transporter associated with antigen processing (TAP)1/TAP2 heterodimeric complexes. Instead, processing occurs within the endoplasmic reticulum by a novel mechanism involving signal pepsidase (SP) and signal peptide peptidase (SPP). Although lung cancer cells bearing the ppCT(16-25) epitope displayed low levels of TAP, restoration of TAP expression by interferon (IFN)-γ treatment or by TAP1/TAP2 gene transfer inhibited ppCT antigen presentation. Thus, the ppCT(16-25) human tumor epitope requires low TAP expression for efficient presentation. These results indicate that emerging SP-generated peptides represent alternative T cell targets that permit cytotoxic T lymphocytes to destroy TAP-impaired tumors, a process that helps to overcome tumor escape from CD8(+) T cell immunity. Additionally, our data suggest that ppCT is a promising candidate for cancer immunotherapy.

Decreased antigenicity of cancer cells is a major problem in tumor immunology. This is often acquired by an expression defect in the TAP. However, it has been reported that certain murine Ags appear on the target cell surface upon impairment of TAP expression. In this study, we identified a human CTL epitope belonging to this Ag category. This epitope is derived from preprocalcitonin (ppCT) signal peptide and is generated within the endoplasmic reticulum by signal peptidase and signal peptide peptidase. Lung cancer cells bearing this antigenic peptide displayed low levels of TAP, but restoration of their expression by IFN-γ treatment or TAP1 and TAP2 gene transfer abrogated ppCT Ag presentation. In contrast, TAP upregulation in the same tumor cells increased their recognition by proteasome/TAP-dependent peptide-specific CTLs. Thus, to our knowledge, ppCT16–25 is the first human tumor epitope whose surface expression requires loss or downregulation of TAP. Lung tumors frequently display low levels of TAP molecules and might thus be ignored by the immune system. Our results suggest that emerging signal peptidase-generated peptides represent alternative T cell targets, which permit CTLs to destroy TAP-impaired tumors and thus overcome tumor escape from CD8+ T cell immunity.

Discovery of a rural settlement of the Hallstatt D/La Tène A period in Toury (France, Eure-et-Loir) during archaeological trial excavations, Découverte d'un habitat rural du Hallstatt final ou de la Tène ancienne à Toury (Eure-et-Loir) dans le cadre d'un diagnostic archéologique

Last part of an archaeological trial in the manor house of the castle of Senonches (France, Eure-et-Loir), having led to the discovery of latrines and new conclusions about the chronology of this hous and the curtain wall; Dernière tranche du diagnostic sur le logis du château de Senonches (Eure-et-Loir), ayant permis la découverte de latrines et de proposer une chronologie détaillée de la construction de l'enceinte et du logis

International audience; Early responses of Tregs and effector T cells (Teffs) to their first encounter with tumor cells have been poorly characterized. Here we have shown, in both implanted and in situ-induced mouse tumor models, that the appearance of tumor cells is immediately sensed by CD44hi memory Tregs that are specific for self antigens. The rapid response of these Tregs preceded and prevented activation of naive antitumor Teffs. The relative speed of the Treg versus the Teff response within the first 2-4 days determined the outcome of the antitumor immune response: tolerance or rejection. If antitumor memory Teffs were present at the time of tumor emergence, both Tregs and Teffs were recruited and activated with memory kinetics; however, the Tregs were unable to control the Teffs, which eradicated the tumor cells. This balance between effector and regulatory responses did not depend on the number of Tregs and Teffs, but rather on their memory status. Thus, in the natural setting, dominant tolerogenic immunosurveillance by self-specific memory Tregs protects tumors, just as it protects normal tissues. More generally, our results reveal that the timing of Treg and Teff engagement, determined by their memory status, is an important mode of regulation of immune responses.

National audience

Preliminary survey realised in Châteaudun (France, Eure-et-Loir), haviung led to the discovery of an enclosure of the La Tène C/D era., Diagnostic archéologique réalisé en septembre 2009 à Châteaudun (Eure-et-Loir), ayant permis la mise au jour d'un enclos de La Tène moyenne/finale

rapport de diagnostic; Preliminary survey realised in Châteaudun (France, Eure-et-Loir), haviung led to the discovery of an enclosure of the La Tène C/D era.; Diagnostic archéologique réalisé en septembre 2009 à Châteaudun (Eure-et-Loir), ayant permis la mise au jour d'un enclos de La Tène moyenne/finale

Preliminary survey realised in Châteaudun (France, Eure-et-Loir), haviung led to the discovery of an enclosure of the La Tène C/D era., Diagnostic archéologique réalisé en septembre 2009 à Châteaudun (Eure-et-Loir), ayant permis la mise au jour d'un enclos de La Tène moyenne/finale

ill.

International audience

3 fig. [En ligne], mis en ligne le 30 mai 2008. URL : http://racf.revues.org//index654.html.; International audience