Our projects aim at developing innovative therapeutic strategies against aggressive cancers, especially malignant pleural mesothelioma, by combining their direct cytotoxicity with induction of specific antitumor immune responses.
Over the years, our group has become specialized in studying tumor cell death induced by anticancer therapies. Immunogenic cell death is defined by the release of danger signals that stimulate immune cells so they can participate to therapeutic effects. Several clinical studies showed that some antitumor treatments such as chemotherapies or so-called “oncolytic” viruses are able to trigger specific immune responses after inducing immunogenic death of tumor cells, in particular by activating dendritic cells and T cells that have central roles in immunity.
Our team has an expertise in developing novel therapies that exploit immunogenic cell death induction in order to improve the treatment of cancers that are known to be resistant to conventional therapies, like mesothelioma, a type of cancer due to exposure to asbestos. Two main approaches are currently being developed in our laboratory: epigenetic therapy and cancer virotherapy.
The first approach deals with the identification, vectorization and use of new epigenetic drugs. These agents are able to kill tumor cells but also to edit in these cells changes in DNA methylation or histone acetylation. Our results show that these molecules, developed in collaboration with Dr P. Bertrand (CNRS, Poitiers), have, in addition to their cytotoxic activities, interesting immunological properties such as the ability to induce the expression of new antigens by tumor cells. Along with Dr Elena Ishow (Université de Nantes), we also work on the development of vectors for these molecules to address them directly to the tumor in order to increase their efficacy and diminish potential side effects.
Our second approach consists in the use of oncolytic viruses that are able to target specifically tumor cells without harming the healthy ones. We mainly focus on the use of an attenuated strain of measles virus, produced by the group of Dr F. Tangy (Institut Pasteur, Paris), of which we demonstrated the antitumor properties against mesothelioma, melanoma, and lung and colorectal adenocarcinomas. When infected, these different types of tumor cells are induced toward immunogenic cell death that allows activation of several immune populations, for example myeloid and plasmacytoid dendritic cells that are able to activate cytotoxic T cell responses by cross-presenting tumor antigens.
Finally, we also work on better understanding the development and evolution of mesothelioma. Over the years, we created a biocollection from patient samples that helps us in this purpose. In particular, we try to identify new diagnostic and prognostic markers for mesothelioma. The last we recently identified, CCL2, is involved in the recruitment of M2 macrophages that are immune cells participating in tumor development and resistance to treatments. We also work on original animal models that allow both fundamental research and testing of therapeutic approaches developed in the laboratory to validate their efficacy. These different aspects open new perspectives for the development of targeted therapies against mesothelioma and other aggressive cancers.
M. Grégoire, DR INSERM
C. Blanquart, CR,CNRS
D. Pouliquen, CR INSERM
JF Fonteneau CR INSERM
N. Boisgerault, CR INSERM
T. Delaunay, Doctorant
T. Blondy, Doctorant
C. Linot, Doctorant
J. Nader, Doctorant
F. Allagui, Doctorant
T. Petithomme, Master 2
M. Talatizi, Master 2
S. Deshayes, TR CNRS
D. Coulais, IE INSERM
N. Guyon, AI CDD INSERM
V. Dehame TR, CDI CHU
L. Cellerin, PH
A.L. Chene, AHU CHU
C. Liddell, AHU CHU
C. Sagan, PH CHU
– Allagui F, Achard C, Panterne C, Combredet C, Labarrière N, Dréno B, Elgaaied AB, Pouliquen D, Tangy F, Fonteneau JF, Grégoire M, Boisgerault N. Modulation of the Type I Interferon Response Defines the Sensitivity of Human Melanoma Cells to Oncolytic Measles Virus. Current Gene Therapy. 2017 Jan 2. [Sous presse]
– Achard C, Guillerme JB, Bruni D, Boisgerault N, Combredet C, Tangy F, Jouvenet N, Grégoire M, Fonteneau JF. Oncolytic measles virus induces Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by human myeloid and plasmacytoid dendritic cells. Oncoimmunology. (2016) [Sous presse]
– Chéné AL, d’Almeida S, Blondy T, Tabiasco J, Deshayes S, Fonteneau JF, Cellerin L, Delneste Y, Grégoire M, Blanquart C. Pleural Effusions from Patients with Mesothelioma Induce Recruitment of Monocytes and Their Differentiation into M2 Macrophages. Journal of Thoracic Oncology. (2016)
– Roulois D, Deshayes S, Guilly MN, Nader JS, Liddell C, Robard M, Hulin P, Ouacher A, Le Martelot V, Fonteneau JF, Grégoire M, Blanquart C, Pouliquen DL. Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine. Oncotarget. (2016)
El Bahhaj F, Denis I, Pichavant L, Delatouche R, Collette F, Linot C, Pouliquen D, Grégoire M, Héroguez V, Blanquart C, Bertrand P. Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy. Theranostics. (2016)
– Achard C, Boisgerault N, Delaunay T, Roulois D, Nedellec S, Royer PJ, Pain M, Combredet C, Mesel-Lemoine M, Cellerin L, Magnan A, Tangy F, Grégoire M, Fonteneau JF. Sensitivity of human pleural mesothelioma to oncolytic measles virus depends on defects of the type I interferon response.
– Boisgerault N, Guillerme JB, Pouliquen D, Mesel-Lemoine M, Achard C, Combredet C, Fonteneau JF, Tangy F, Grégoire M. Natural oncolytic activity of live-attenuated measles virus against human lung and colorectal adenocarcinomas. Biomed Research International. (2013)
– Gueugnon F, Denis I, Pouliquen D, Collette F, Delatouche R, Héroguez V, Grégoire M, Bertrand P, Blanquart C. Nanoparticles produced by ring-opening metathesis polymerization using norbornenyl-poly(ethylene oxide) as a ligand-free generic platform for highly selective in vivo tumor targeting. Biomacromolecules. (2013)
– Guillerme JB, Boisgerault N, Roulois D, Ménager J, Combredet C, Tangy F, Fonteneau JF, Grégoire M. Measles virus vaccine-infected tumor cells induce tumor antigen cross-presentation by human plasmacytoid dendritic cells. Clinical Cancer Research. (2013)
– Blanquart C, Gueugnon F, Nguyen JM, Roulois D, Cellerin L, Sagan C, Perigaud C, Scherpereel A, Gregoire M. CCL2, galectin-3, and SMRP combination improves the diagnosis of mesothelioma in pleural effusions. Journal of Thoracic Oncology. (2012)
– Leclercq S, Gueugnon F, Boutin B, Guillot F, Blanquart C, Rogel A, Padieu M, Pouliquen D, Fonteneau JF, Grégoire M. A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma. European Respiratory Journal. (2011)