Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation.

Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.Uruguay INNOVA 2, Fondo Maria Viñas and Clemente Estable from ANII, as well as grants from CABBIO, PEDECIBA, ECOS-SUD and FOCEM (MERCOSUR Structural Convergence Fund), COF 03/11 to MH, The Harry J Lloyd Foundation to MRG and the Instituto Nacional del Cancer to YDM, Agencia de Promoción Científica y Tecnológica to GAR and MRG, Fundación Bunge & Born and Fundación Sales to GA

A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4+ T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4+ T cell hybridomas were generated from inflamed tissue–derived CD4+ T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0–specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3–5 wk of age. This abrupt disease was associated with the production of interferon γ by P0-specific T cells and a lack of CD4+ Foxp3+ regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy

L'améloblastome mandibulaire (prise en charge au CHU d'Accra, Ghana)

L Améloblastome est la tumeur odontogène la plus fréquente (11%), sa localisation est le plus souvent mandibulaire (81%) et il survient majoritairement sur des sujets âgés de 20 à 40 ans, sans aucune préférence sexuelle. Sur le plan anatomo-clinique, on distingue une forme extra osseuse (améloblastome Périphérique) et une forme intra-osseuse qui est la plus habituelle (améloblastome multikystique ou unikystique). Son diagnostic est établi par l histologie et l anatomopathologie, car d un point de vue clinique et radiologique l améloblastome ne présente pas de signe pathognomonique. Au sein de la grande famille des tumeurs odontogènes, l améloblastome est assez singulier. Présentant histologiquement un caractère bénin, cliniquement il montre une évolution lente à bas bruit, avec un fort potentiel d agressivité, une capacité à récidiver. Face à ces caractéristiques particulières, la prise en charge de l améloblastome s avère être un challenge, si il n est pas diagnostiqué précocement. Dans ce travail, on a pu noter que dans le Centre Hospitalo-Universitaire d Accra, l améloblastome représente 82% des tumeurs odontogènes traitées. Les cas rencontrés sont très souvent avancés, amenant les chirurgiens à procéder à des chirurgies radicales, suivies d un travail de reconstruction de la mandibule de grande envergure comme le montre les cas cliniques présentés. L amélioration de l arsenal thérapeutique avec l avènement de la solution de Carnoy a fait évoluer la tendance vers une chirurgie plus conservatrice (énucléation). Néanmoins, certains obstacles empêchent la diminution de l incidence d améloblastomes géants : la place accordée aux guérisseurs traditionnels, l assurance de santé publique pas assez efficace, la prise de conscience de la population de visite annuelle chez le chirurgien dentiste, et le manque d établissements et de professionnels de santé.LILLE2-UFR Odontologie (593502202) / SudocSudocFranceF

Identification et étude de nouveaux médiateurs du rejet et de l'induction de tolérance dans un modèle d'allogreffe chez le rat

La connaissance approfondie des mécanismes immunologiques menant au rejet ou à la tolérance d'une allogreffe représente un enjeu capital pour améliorer le succès de la transplantation d'organes chez l'homme, avec pour objectif d'éviter les traitements immunosuppresseurs. La première partie de cette thèse a été consacrée à l'étude du rôle d'une nouvelle molécule de la famille du TNF, TRANCE, dans le rejet d'allogreffe vascularisée chez le rat. Nous montrons que la voie TRANCE-RANK participe aux mécanismes du rejet aigu ainsi qu'au développement des lésions de rejet chronique, indépendament de la voie CD40L-CD40. La seconde partie, constituant l'objectif principal de cette thèse, consistait à isoler des gènes spécifiquement exprimés dans des allogreffes cardiaques dans un modèle d'induction de tolérance par transfusion de sang du donneur (TSD) chez le rat. Une méthodologie de recherche de gènes différentiellement exprimés a été mise en place, en utilisant notamment les techniques d'Hybridation Soutractive Suppressive et de PCR quantitative en temps réel. Nous montrons que la chimiokine Fractalkine et son récepteur CX3CR1 son fortement exprimés dans les greffons tolérés, et que les cellules CD8+ du receveur, requises pour la tolérance, sont responsables de cette induction. Nous avons d'autre part identifié une molécule de fonction inconnue, que nous avons appelée TORID (TOlerance-Related and InduceD transcript), puis démontré son appartenance à la famille du CD20. TORID est localisée dans l'enveloppe nucléaire des cellules dendritiques et des macrophages. Son expression est associée à l'état d'inactivation de ces cellules. L'ensemble des ces résultats contribuent à une meilleure compréhension des mécanismes gouvernant le rejet ou l'induction de tolérance dans ce modèle d'allogreffeUnderstanding of immune mechanisms leading to allograft rejection or tolerance is essential to improve organ transplantation in human, with the aim to avoid immunosuppressive treatments. The first part of this thesis is devoted to the study of the role of a new TNF family member, TRANCE, in allograft rejection in the rat. We show that the TRANCE-RANK pathway participates in acute rejection processes as well as in the development of CD40L-independent chronic rejection. The second part, representing the main objective of this thesis, consists in isolating genes specifically expressed in cardiac allografts in a rat model of tolerance induction by donor-specific blood transfusions (DST). We have set up a methodology of gene searching using suppressive subtractive hybridization and real-time quantitative PCR. We show that the chemokine Fractalkine and its receptor CX3CR1 are strongly expressed in tolerated grafts, and that host CD8+ cells, which are required for tolerance, control this induction. Moreover, we have identified a molecule of unknown function which we named TORID (TOlerance-Related and InduceD transcript). We show that TORID belongs to the CD20 family and is localized at the nuclear envelope of dendritic cells and macrophages. TORID expression is associated with the inactivation state of these cells. Taken together, these results contribute to a better understanding of the mechanisms governing rejection or tolerance induction in this modelNANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Successful treatment with yttrium-90 microspheres in a metastatic breast cancer patient and sclerosing cholangitis.

Breast cancer is the most common malignancy occurring in women worldwide. More than 90% of patients present with localized disease are treated with curative intent; however, recurrence can occur with development of metastatic lesions. Frequently associated with extra-hepatic lesions, localized treatments (surgery or stereotaxic body radiotherapy) are rarely proposed in liver lesions. Y radioembolization has extensively been evaluated in colorectal cancer, but its role in breast cancer with isolated liver metastases remains largely unknown. Pre-existing liver diseases are known risk factors for Y induced liver toxicity. Not considered as an excluding factor for this treatment, data are limited regarding its safe use with cholangitis. We report a successful control of liver metastases by Y radioembolization in a breast cancer patient

Generation of a Double KO Mouse by Simultaneous Targeting of the Neighboring Genes Tmem176a and Tmem176b Using CRISPR/Cas9: Key Steps from Design to Genotyping

International audienceThe CRISPR/Cas9 system has been tailored to a revolutionary genetic tool because of its remarkable simplicity and efficacy. While complex genome editing in the mouse since the 1990s has been dominated by the use of embryonic stem (ES) cells, CRISPR/Cas9 now offers a versatile and fast approach to precisely modify virtually any DNA regions directly in mouse zygotes. Yet, this relative simplicity does not preclude a conscientious preparatory work that is often neglected when initiating a project. Here, we describe the key steps leading to successful generation of a double knockout (KO) mouse by simultaneously targeting two homolog genes, Tmem176a and Tmem176b, which are located in the same genomic locus. Additionally, we show that similar efficiency can be obtained in a mixed genetic background or directly in the C57BL/6 inbred strain. Thus, presented as a detailed case study that should be helpful to the non-specialists, we focus on the genotyping strategy to anticipate the various possibilities

Long-lasting benefit on multimodal treatment combining osimertinib and stereotaxic radiotherapy for metastatic non-small cell lung cancer with the EGFR exon 20 insertion 773-774 HVdelinsLM: a case report.

A non-small-cell-lung-cancer patient with cerebral metastasis presenting an atypical exon 20 mutation in the EGFR gene had a long-lasting tumor cotrol on mulimodal treatment with osimertinib and stereotaxic radiotherapy on oligoprogressing lesions. Most exon-20 mutations are resistant to first, second and third generation EGFR-directed TKI. This case was discussed on our molecular tumour board. As the more specific exon-20 targeted therapies were not yet available and as sporadic short responses on the third generation EGFR-directed TKI, osimertinib had been described, the patient started osimertinib. She had a prolonged tumoral response on Osimertinib. The patient is still asymptomatic up to 32 months after initiating the medication. This case confirms that not all exon20 EGFR mutations are equal to osimertinib and that the localization of the exon 20 insertion mutation is probably important to consider when treating EGFR mutated NSCLC. The long-term clinical benefit can be maintained through stereotactic radiotherapy on focal progressive lesions

The Intracellular Ion flux mediated by TMEM176A and TMEM176B is involved in the regulation of Dendritic Cell Functions

International audienceThe regulation of immune cells by intracellular ion channels remains poorly explored. Here we investigated the role of two cation channels encoded by Tmem176a and Tmem176b that are highly expressed in myeloid cells in the immune system. To avoid any functional compensation, we generated double knock-out (DKO) mice, allowing simultaneous deletion of these two highly redundant and coregulated genes using the CRISPR-Cas9 system. The absence of Tmem176a/b significantly impacted antigen processing and presentation to CD4+ T cells in vivo and selectively altered cytokine production by dendritic cells (DCs). Using a novel real-time fluorescence-based system to analyze intracellular trafficking we found that both channels co-localized in highly dynamic post-Golgi vesicles preferentially interacting with, but not accumulating in, acidic organelles. Thus, these results highlight the importance of TMEM176A/B-mediated cation flux for the fine regulation of DC biology