Differential regulation of IL-22BP in Crohn’s disease versus ulcerative colitis

International audienc

A subset of dendritic cells as a major and constitutive source of IL-22BP

Poster presentationInternational audienc

Clinical Study Adoptive TIL Transfer in the Adjuvant Setting for Melanoma: Long-Term Patient Survival

Two first analyses of our clinical trial on TIL as adjuvant therapy for melanoma were published in 2002 and 2007. We present here an update of the clinical results after a 17-year median followup. In this trial, disease-free patients were randomly assigned to receive either TIL/IL-2 or IL-2. The relapse-free survival (RFS) was the primary objective. Eighty-eight patients were enrolled. A new analysis performed in May 2013 did not show significant changes in RFS or OS duration. However, our first finding on the association between the number of invaded lymph nodes and TIL effectiveness was strengthened. The Cox model adjusted on this interaction showed for the first time a significant treatment effect when considering the overall population, both on the RFS and OS. Patients treated with TIL had a longer RFS ( = 0.023) or OS ( = 0.020). This study being with a very long followup (17 years), confirmed the association between TIL effectiveness and the number of invaded lymph nodes, indicating that a low tumor burden could be a crucial factor enhancing the curative effect of TIL in possible microscopic residual disease. Moreover, we confirmed that a prolonged survival was associated with the presence of specific TIL and a decrease in Foxp3 expression

CD4CD8αα Lymphocytes, A Novel Human Regulatory T Cell Subset Induced by Colonic Bacteria and Deficient in Patients with Inflammatory Bowel Disease

It has become evident that bacteria in our gut affect health and disease, but less is known about how they do this. Recent studies in mice showed that gut Clostridium bacteria and their metabolites can activate regulatory T cells (Treg) that in turn mediate tolerance to signals that would ordinarily cause inflammation. In this study we identify a subset of human T lymphocytes, designated CD4CD8αα T cells that are present in the surface lining of the colon and in the blood. We demonstrate Treg activity and show these cells to be activated by microbiota; we identify F. prausnitzii, a core Clostridium strain of the human gut microbiota, as a major inducer of these Treg cells. Interestingly, there are fewer F. prausnitzii in individuals suffering from inflammatory bowel disease (IBD), and accordingly the CD4CD8αα T cells are decreased in the blood and gut of patients with IBD. We argue that CD4CD8αα colonic Treg probably help control or prevent IBD. These data open the road to new diagnostic and therapeutic strategies for the management of IBD and provide new tools to address the impact of the intestinal microbiota on the human immune system

Etude retrospective de 60 cas de lymphome NK/T et T de présentation ORL (aspects cliniques, morphologiques et phénotypiques avec analyse de l'expression des effecteurs et des inhibiteurs de l'apoptose)

PARIS7-Villemin (751102101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Mécanismes cellulaires et moléculaires des perturbations du renouvellement de l'épithelium intestinal et de l'oncogenèse au cours des maladies inflammatoires chroniques de l'intestin

L'homéostasie de la barrière intestinale peut-être rompue au cours de 2 processus physiopathologiques : 1) la prolifération incontrôlée des cellules épithéliales au cours d'un processus de régénération cicatricielle pouvant initier un processus d'oncogenèse, et 2) une perte cellulaire accélérée suite à une réponse inflammatoire de la muqueuse. Ce travail de thèse est divisé en 2 parties. L'une, clinico-pathologique et biologique, est fondée sur l'exploitation d'une population de patients atteints de maladie inflammatoire chronique de l intestin (MICI) et ayant développé des lésions coliques selon la séquence inflammation / régénération / dysplasie / cancer. Cette approche a permis de valider des marqueurs phénotypiques et génotypiques susceptibles d'être associés à chacune des étapes du processus d oncogenèse. L'autre, fondamentale, est fondée sur l'exploitation d'un nouveau modèle de culture d'explants de muqueuse colique humaine normale et a permis de recréer ex vivo l initiation d une réponse inflammatoire de type Th1. Ces 2 approches ont apporté des éléments nouveaux : - Le remodelage épithélial au cours des MICI est associé à la voie des tumeurs festonnées, voie de carcinogenèse récemment décrite dans les cancers du colon sporadiques, définie par une signature morphologique et oncogénétique originale (mutation de BRAF et statut MSI de la tumeur) (article 1). - La régénération épithéliale au cours des MICI coïncide avec l'expression du récepteur de la neurotensine, NTS1. Cette expression est régulée soit par son propre ligand, la neurotensine, soit par la b caténine (article 2).- L intégrité de la barrière épithéliale intestinale chez l'homme est dépendante de 2 cytokines dites cytokines du mutualisme , l IL10 et le TGFb, produites par les cellules résidentes de la muqueuse. En l'absence d IL10, le LPS endogène déclenche une réponse immunitaire de type Th1 à l origine de la rupture de la barrière épithéliale (article 3). En conclusion, les approches que nous avons développées, à l origine de résultats originaux, serviront à mieux définir les rapports entre l inflammation intestinale et l oncogenèse colorectaleThe intestinal mucosa homeostasis can be disturbed during two related physiopathological process: 1) an uncontrolled proliferation of epithelial cells during inflammatory repair leading to oncogenesis, and 2) an accelerated cellular loss during intestinal inflammatory response. This work is divided into 2 parts. The first approach is based a cohort of patients suffering from inflammatory bowel disease (IBD) with lesions evolving towards cancer through the inflammation / regeneration / dysplasia / cancer sequence. This approach led us to validate several phenotypic and genotypic markers likely to be associated with the stepwise process of oncogenesis. The other approach is based on the exploitation of a new explant culture model of human normal colonic mucosa that led us to recreate ex vivo the initiation of a Th1 inflammatory response. New findings resulting from these 2 approaches are as follows: - Epithelial remodelling during IBD is associated with the serrated pathway of oncogenesis, first described in sporadic colon cancer. This pathway is defined by a morphological and oncogenetic signature (BRAF mutation and MSI status of the tumor) (article 1). - Epithelial regeneration during IBD is associated with the expression of the neurotensin receptor, NTS1. NTS1 expression is regulated by its ligand, neurotensin or by b catenin (article 2). - Finally, the human intestinal epithelial barrier integrity depends on 2 immunoregulatory cytokines, IL10 and TGFb, produced by mucosal resident cells. After IL10 depletion, endogenous LPS triggers a Th1 immune response leading to epithelial barrier disruption (article 3). In conclusion, the approaches developed led to new findings which will help define the mechanistic link between intestinal inflammation and oncogenesis.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Pembrolizumab for the treatment of colorectal cancer

International audienceIntroduction: Colorectal cancer (CRC) is one of the most frequent and lethal cancers in the world, and therapies are still insufficient. Immune checkpoint inhibitors (ICI) in metastatic CRC (mCRC) have not revolutionized treatment to the extent that they have in melanoma or renal carcinoma. Their use is limited to a molecular niche of mCRC with microsatellite instability (MSI). This review summarizes clinical data published with pembrolizumab in mCRC and also tries to identify potential new strategies. Areas covered: This paper focuses on pembrolizumab in mCRC. We screened all trials on PubMed and ClinicalTrials.gov and describe the most significant ones in our opinion. Expert opinion: Pembrolizumab seems to be effective in tumors with MSI-high status. It defines a new horizon for therapeutic strategy called 'agnostic' medicine. For microsatellite stable (MSS) colorectal cancers, the future challenge will be to successfully redraw the immune microenvironment to make it immunogenic with new therapeutic combinations, including IC

A multiparametric approach to monitor the effects of γ-secretase inhibition along the whole intestinal tract

γ-secretase inhibitors (GSIs) have been recently proposed as chemopreventive agents in gastrointestinal neoplasia, because they lead, through inhibition of the Notch signaling pathway, to goblet cell conversion in some intestinal adenomas of the ApcMin mice, and halt epithelial cell proliferation. In this study, we examine in depth, in normal mice, the effects of a GSI, dibenzazepine (DBZ), intraperitoneally administered for 8 days at a non toxic dose, on the gene expression pattern of secretory mucin (MUC), goblet cell conversion, organization of the crypt structural-proliferative units, stem cell niche and apoptotic compartments, along the entire length of the small intestine and colon. We demonstrate that DBZ elicits a homogeneous goblet cell conversion all along the mouse intestinal tract, associated with an overexpression of the gene Muc2 without ectopic expression of the gastric genes Muc5ac and Muc6, and with the emergence of lysozyme-positive ‘intermediate cells’ in the colon. Furthermore, DBZ treatment induces a heterogeneous reorganization of the crypt structural-proliferative units along the intestinal tract and of the stem cell niche in the colon, without disturbing the apoptotic compartment. These findings point to uncoupled effects of a GSI on goblet cell conversion and reorganization of the intestinal crypt structural-proliferative units and stem cell niche, and suggest caution in the use of GSIs as chemopreventive agents for intestinal neoplasia

The double stranded RNA analog poly-IC elicits both robust IFN-λ production and oncolytic activity in human gastrointestinal cancer cells

International audienceCopyright: Bou-Hanna et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Purpose: Type III IFN (IFN-λ) is the dominant frontline response over type I IFN in human normal intestinal epithelial cells upon viral infection, this response being mimicked by the dsRNA analog poly-IC. Poly-IC also induces cell death in murine intestinal crypts ex vivo. Here we examined whether these innate defense functions of normal intestinal epithelial cells are recapitulated in gastrointestinal carcinoma cells so that they could be harnessed to exert both immunoadjuvant and oncolytic functions, an unknown issue yet. Experimental design: Four human gastrointestinal carcinoma cell lines versus the Jurkat lymphoma cell line were used to assess the effects of intracellular poly-IC on i) IFN-λ secretion and cell proliferation and ii) role of NFκB signaling using the NFκB inhibitory peptide SN50 as a screening probe and a siRNA approach. Results: Poly-IC induced in all cell lines except Jurkat both a robust IFN-λ secretion and a cytoreductive effect on adherent cells, restricted to proliferating cells and associated with cellular shedding and reduced clonogenicity of the shed cells. Collectively these findings demonstrate the oncolytic activity of poly-IC. Inhibiting NFκB in T84 cells using a siRNA approach decreased IFN-λ production without protecting the cells from the poly-IC oncolytic effects. In line with these findings IFN-λ, that upregulated the anti-viral protein MxA, was unable per se to alter T84 cell proliferation. Conclusion: Our demonstration that poly-IC-induced concomitant recapitulation of two innate functions of normal intestine, i.e. IFN-λ production and cell death, by human gastrointestinal cancer cells opens new perspectives in gastrointestinal cancer treatment