Study of different oncolytic viruses for cancer immunotherapy : mechanisms of tumor sensitivity and effects on the immune response

L’immunothérapie oncolytique exploite les propriétés lytiques et immunogènes des virus oncolytiques (OV). Ces virus répliquent et lysent sélectivement les cellules tumorales sans nuire aux tissus sains. Au cours de ma thèse, j’ai identifié la délétion bi-allélique des gènes codant les interférons de type I (IFN I, IFN-α et -β) comme étant le défaut le plus fréquent de la réponse antivirale IFN I dans le mésothéliome pleural malin (MPM). Ces altérations rendent les cellules tumorales permissives au virus atténué oncolytique de la rougeole. J’ai aussi montré que cette perte des gènes des IFN I est fréquente dans les cancers où la délétion du gène suppresseur de tumeur CDKN2A est impliquée (glioblastome, cancer de l’oesophage). Nous sommes donc les premiers à établir le lien entre les délétions des gènes des IFN I et la sensibilité des cellules tumorales à un OV. Ce lien pourrait probablement servir de marqueur prédictif de l’efficacité de l’immunothérapie oncolytique. J’ai ensuite évalué la forte activité oncolytique in vitro et in vivo contre le MPM du virus de la vaccine modifié VVTK-RR- délété des gènes codant la thymidine kinase et la ribonucléotide réductase afin d’assurer sa spécificité. Enfin, j’ai démontré un nouveau mécanisme de stimulation de la réponse immunitaire anti-tumorale humaine par différents OV. En effet, en lysant les cellules tumorales, les OV provoquent le transfert intercellulaire d’antigènes tumoraux tels que NYESO- 1 qui induit ou renforce la présentation de ces antigènes à des lymphocytes T CD4+ cytotoxiques spécifiques. Dans l’ensemble, mes travaux de thèse permettent une meilleure compréhension de l’activité oncolytique de différents virus et de leurs effets sur la réponse immunitaire anti-tumorale.Oncolytic immunotherapy exploits the lytic and immunogenic properties of oncolytic viruses (OV). These viruses selectively replicate in and lyze tumor cells without harming healthy tissues. During my thesis, I first identified the bi-allelic deletion of genes encoding type I interferons (IFN I, IFN-α et -β) as the most frequent defect in the IFN I antiviral response in malignant pleural mesothelioma (MPM). These alterations make the tumor cells permissive to attenuated oncolytic measles virus that subsequently provokes their lysis. I also showed that this loss of IFN I genes is common to cancers for which the deletion of the tumor suppressor gene CDKN2A is critical (glioblastoma, esophageal cancer). This is the first report showing a link between the deletion of IFN I genes and the sensitivity of tumor cells to OV. This link could be used as a predictive marker of the efficacy of oncolytic immunotherapy. I then demonstrated in vitro and in vivo a strong oncolytic activity against MPM of the VVTK-RR- modified vaccinia virus deleted from the genes encoding the thymidine kinase and the ribonucleotide reductase. This OV is thus of particular interest for oncolytic immunotherapy of MPM. Finally, I demonstrated a new mechanism by which different OV favor the human anti-tumor immune response. By lyzing tumor cells, OV allow the intercellular transfer of tumorassociated antigens such as NY-ESO-1 and induce or reinforce the presentation of these antigens to specific cytotoxic CD4+ T cells. Overall, my PhD work provides a better understanding of both the oncolytic activity of different viruses and their effects on the antitumor immune response

Study of different oncolytic viruses for cancer immunotherapy : mechanisms of tumor sensitivity and effects on the immune response

L’immunothérapie oncolytique exploite les propriétés lytiques et immunogènes des virus oncolytiques (OV). Ces virus répliquent et lysent sélectivement les cellules tumorales sans nuire aux tissus sains. Au cours de ma thèse, j’ai identifié la délétion bi-allélique des gènes codant les interférons de type I (IFN I, IFN-α et -β) comme étant le défaut le plus fréquent de la réponse antivirale IFN I dans le mésothéliome pleural malin (MPM). Ces altérations rendent les cellules tumorales permissives au virus atténué oncolytique de la rougeole. J’ai aussi montré que cette perte des gènes des IFN I est fréquente dans les cancers où la délétion du gène suppresseur de tumeur CDKN2A est impliquée (glioblastome, cancer de l’oesophage). Nous sommes donc les premiers à établir le lien entre les délétions des gènes des IFN I et la sensibilité des cellules tumorales à un OV. Ce lien pourrait probablement servir de marqueur prédictif de l’efficacité de l’immunothérapie oncolytique. J’ai ensuite évalué la forte activité oncolytique in vitro et in vivo contre le MPM du virus de la vaccine modifié VVTK-RR- délété des gènes codant la thymidine kinase et la ribonucléotide réductase afin d’assurer sa spécificité. Enfin, j’ai démontré un nouveau mécanisme de stimulation de la réponse immunitaire anti-tumorale humaine par différents OV. En effet, en lysant les cellules tumorales, les OV provoquent le transfert intercellulaire d’antigènes tumoraux tels que NYESO- 1 qui induit ou renforce la présentation de ces antigènes à des lymphocytes T CD4+ cytotoxiques spécifiques. Dans l’ensemble, mes travaux de thèse permettent une meilleure compréhension de l’activité oncolytique de différents virus et de leurs effets sur la réponse immunitaire anti-tumorale.Oncolytic immunotherapy exploits the lytic and immunogenic properties of oncolytic viruses (OV). These viruses selectively replicate in and lyze tumor cells without harming healthy tissues. During my thesis, I first identified the bi-allelic deletion of genes encoding type I interferons (IFN I, IFN-α et -β) as the most frequent defect in the IFN I antiviral response in malignant pleural mesothelioma (MPM). These alterations make the tumor cells permissive to attenuated oncolytic measles virus that subsequently provokes their lysis. I also showed that this loss of IFN I genes is common to cancers for which the deletion of the tumor suppressor gene CDKN2A is critical (glioblastoma, esophageal cancer). This is the first report showing a link between the deletion of IFN I genes and the sensitivity of tumor cells to OV. This link could be used as a predictive marker of the efficacy of oncolytic immunotherapy. I then demonstrated in vitro and in vivo a strong oncolytic activity against MPM of the VVTK-RR- modified vaccinia virus deleted from the genes encoding the thymidine kinase and the ribonucleotide reductase. This OV is thus of particular interest for oncolytic immunotherapy of MPM. Finally, I demonstrated a new mechanism by which different OV favor the human anti-tumor immune response. By lyzing tumor cells, OV allow the intercellular transfer of tumorassociated antigens such as NY-ESO-1 and induce or reinforce the presentation of these antigens to specific cytotoxic CD4+ T cells. Overall, my PhD work provides a better understanding of both the oncolytic activity of different viruses and their effects on the antitumor immune response

Manifestations buccales du syndrome de Job-Buckley (à propos d'un cas clinique)

LYON1-BU Santé Odontologie (693882213) / SudocSudocFranceF

Uniform boundary stabilization of a high-order finite element space discretization of the 1-d wave equation

The objective of this work is to propose and analyze numerical schemes for solving boundary control problems or data assimilation problems by observers for wave propagation problems. The efficiency of the considered control or data assimilation strategy relies on the exponentially stable character of the underlying system. Therefore, the aim of our work is to propose a discretization process that allows preserving the exponential stability at the discrete level when using high-order spectral finite element approximation. The main idea is to add a stabilizing term to the wave equation that dampens the spurious oscillatory components of the solutions. This term is based on a discrete multiplier analysis that gives us the exponential stability of the semi-discrete problem at any order without affecting the approximation properties

Mathematical analysis of an observer for solving inverse source wave problem

The objective of this work is to propose a method using observers to estimate a source term of a wave equation from internal measurements in a subdomain. The first part of the work consists in proving an identifiability result from classical observability conditions for wave equations. We show that the source reconstruction is an ill-posed inverse problem of degree 1 or 2 depending on the measurements type. This inverse problem is solved using observers -- a sequential strategy -- that is proven to be equivalent to a minimization of a cost functional with Tikhonov regularization

Mathematical analysis of an observer for solving inverse source wave problem

The objective of this work is to propose a method using observers to estimate a source term of a wave equation from internal measurements in a subdomain. The first part of the work consists in proving an identifiability result from classical observability conditions for wave equations. We show that the source reconstruction is an ill-posed inverse problem of degree 1 or 2 depending on the measurements type. This inverse problem is solved using observers -- a sequential strategy -- that is proven to be equivalent to a minimization of a cost functional with Tikhonov regularization

Manifestations buccales du syndrome de Job-Buckley : à propos d’un cas

Le syndrome de Job-Buckley, ou hyperimmunoglobulinémie E, est une affection rare, décrite en 1966, vraisemblablement due à un dysfonctionnement du gène STAT 3. Les manifestations générales sont de type infectieux et eczémateux le plus souvent. Le patient présente également un faciès caractéristique. Dans la cavité buccale, la maladie se traduit par des lésions muqueuses eczémateuses et une prédisposition aux infections dentaires et candidosiques. Devant l’absence de traitement général efficace, la prise en charge bucco-dentaire passe par une mise en état de la cavité buccale, la surveillance des lésions muqueuses et la prévention des infections bactériennes et fongiques

Induction of Immunogenic Tumor Cell Death by Attenuated Oncolytic Measles Virus

International audienceAntitumor virotherapy is a developing approach to treat cancer with oncolytic viruses, namely replicative viruses that exclusively or preferentially infect and kill tumor cells. Attenuated strains of Measles Virus (MV) are now being used as oncolytic viruses in clinical trials to treat several types of cancer. The efficacy of oncolytic viruses is mainly due to their capacity to infect and kill tumor cells, but it has also been demonstrated that their capacity to induce immunogenic cell death can activate an antitumor immune response. In this review, we describe the oncolytic capacity of MV and the concept of Immunogenic Cell Death (ICD). We then review how MV induces immunogenic cell death, which can be beneficial for cancer treatment

A Functional Assay to Determine the Capacity of Oncolytic Viruses to Induce Immunogenic Tumor Cell Death

International audienceOncolytic immunotherapy efficacy relies partially on the induction of immunogenic tumor cell death following infection with oncolytic viruses (OV) to induce an antitumor immune response. Here, we describe a method to determine if an OV is able to induce such an immunogenic tumor cell death. This method consists in testing whether tumor cells lysed by an OV are able to induce the maturation of human monocyte-derived immature dendritic cells (Mo-iDC)