Our projects aim at understanding the tumor microenvironment of aggressive cancers, especially malignant pleural mesothelioma and lung cancer, to develop innovative therapeutic strategies by combining their direct cytotoxicity with induction of specific antitumor immune responses.
Over the years, our team 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, or lung cancer. 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 E. 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, 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.
To improve and develop our innovative therapies, a better understanding of the tumor microenvironment (TME) of thoracic cancers is needed. In the TME, stromal cells are corrupted by malignant cells, creating a permissive microenvironment which drives cancer progression. Our team has an expertise in studying this communication between tumor, immune and stromal cells (e.g. endothelial cells). Several aspects are currently being investigated at our laboratory: direct interaction, soluble factors and extracellular vesicles.
We take advantage of our biocollection of patient samples to identify new soluble factors modulating the TME. Recently, we identified CCL2 as being involved in the recruitment of M2 macrophages, which are immune cells participating in tumor development and resistance to treatments. Soluble factors can also be considered as perfect biomarkers. We recently showed that IL-34, a cytokine involved in macrophage biology, is an independent prognostic factor in mesothelioma.
Other components of the TME communication investigated by our team are extracellular vesicles (EVs). We recently demonstrated that EVs from tumor cells reduce the immune response against them through the transfer of microRNAs (miRNAs) targeting key genes of T cell functions. We are particularly interested in miRNAs enclosed into small EVs called exosomes since we showed that miRNAs are not randomly sorted but are chosen to disseminate and to modulate recipient cells. All cells in the TME secrete EVs and our team also consider EVs from endothelial cells. Beyond their involvement in angiogenesis, metastasis and immune cell recruitment, endothelial cells are important modulators of tumor immune response. We are particularly interested in unraveling how endothelial cells (and their EVs) could modulate the TME and response to treatments.
Marc Grégoire, Head (INSERM)
Christophe Blanquart, Researcher (CNRS)
Nicolas Boisgerault, Researcher (INSERM)
Jean-François Fonteneau, Researcher (INSERM)
Delphine Fradin, Researcher (INSERM)
Lucas Treps, Post-doctorant
Virginie Dehame, Technician (CHU Nantes)
Sophie Deshayes, Technician (CNRS)
Judith Fresquet, Engineer (INSERM)
Jaafar Bennouna, Senior Physician (CHU Nantes)
Laurent Cellerin, Senior Physician (CHU Nantes)
Anne-Laure Chéné, Physician (CHU Nantes)
Murielle Corvaisier-Chiron, Clinical trials (CHU Nantes)
Elvire Pons-Tostivint, Physician (CHU Nantes)
Christine Sagan, Senior Physician (CHU Nantes)
Pierre Autin, PhD Student
Tina Briolay, PhD Student
Camille Chatelain, PhD Student
Morgane Fouet, PhD Student
Marion Grard, PhD Student
Ugo Hirigoyen, PhD Student
Maureen Labbé, PhD Student
Margot Lavy, PhD Student
Thomas Ogor, PhD Student (Université de Montpellier)
Tacien Petithomme, PhD Student
Molecular Cancer (2020) : HAL INSERM 02515300
Kara-Terki L, Treps L, Blanquart C, Fradin D. Critical Roles of Tumor Extracellular Vesicles in the Microenvironment of Thoracic Cancers. International Journal of Molecular Science (2020) : HAL INSERM 02946311
Jean D, Delaunay T, Meiller C, Boisgerault N, Grard M, Caruso S, Blanquart C, Felley-Bosco E, Bennouna J, Tangy F, Grégoire M, Fonteneau JF. Reply to: Oncolytic Viral Therapy for Malignant Pleural Mesothelioma. Journal of Thoracic Oncology (2020) : HAL INSERM 02547453
Blondy T, d’Almeida SM, Briolay T, Tabiasco J, Meiller C, Chéné AL, Cellerin L, Deshayes S, Delneste Y, Fonteneau JF, Boisgerault N, Bennouna J, Grégoire M, Jean D, Blanquart C. Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma. Journal for ImmunoTherapy of Cancer (2020) : HAL INSERM 02913733
Blanquart C, Jaurand MC, Jean D. The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models. Frontiers in Oncology (2020) : HAL INSERM 02518612
Delaunay T, Achard C, Boisgerault N, Grard M, Petithomme T, Chatelain C, Dutoit S, Blanquart C, Royer PJ, Minvielle S, Quetel L, Meiller C, Jean D, Fradin D, Bennouna J, Magnan A, Cellerin L, Tangy F, Grégoire M, Fonteneau JF. Frequent homozygous deletions of type I interferon genes in pleural mesothelioma confer sensitivity to oncolytic measles virus. Journal of Thoracic Oncology (2020) : HAL INSERM 02447160
Vignard V, Labbé M, Marec N, André-Grégoire G, Jouand N, Fonteneau JF, Labarrière N, Fradin D. MicroRNAs in Tumor Exosomes Drive Immune Escape in Melanoma. Cancer Immunology Research (2020) : HAL INSERM 02426329
Boucard J, Briolay T, Blondy T, Boujtita M, Nedellec S, Hulin P, Grégoire M, Blanquart C, Ishow E. Hybrid Azo-fluorophore Organic Nanoparticles as Emissive Turn-on Probes for Cellular Endocytosis. ACS Applied Materials & Interfaces (2019) : HAL INSERM 02281253
Autin P, Blanquart C, Fradin D. Epigenetic Drugs for Cancer and microRNAs: A Focus on Histone Deacetylase Inhibitors. Cancers (Basel) (2019) : HAL INSERM 02315396
Boucard J, Linot C, Blondy T, Nedellec S, Hulin P, Blanquart C*, Lartigue L, Ishow E*. Small Molecule-Based Fluorescent Organic Nanoassemblies with Strong Hydrogen Bonding Networks for Fine Tuning and Monitoring Drug Delivery in Cancer Cells. Small (2018) : HAL INSERM 01885511
Bensaid D, Blondy T, Deshayes S, Dehame V, Bertrand P, Grégoire M, Errami M, Blanquart C. Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma. Clinical Epigenetics (2018) : HAL INSERM 01820890
Smeele P, d’Almeida SM, Meiller C, Chéné AL, Liddell C, Cellerin L, Montagne F, Deshayes S, Benziane S, Copin MC, Hofman P, Le Pimpec-Barthes F, Porte H, Scherpereel A, Grégoire M, Jean D, Blanquart B. Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis. Molecular Cancer (2018) : HAL INSERM 01904612
Delaunay T, Violland M, Boisgerault N, Dutoit S, Vignard V, Münz C, Gannage M, Dréno B, Vaivode K, Pjanova D, Labarrière N, Wang Y, Chiocca E, Le Boeuf F, Bell J, Erbs P, Tangy F, Grégoire M, Fonteneau JF. Oncolytic viruses sensitize human tumor cells for NY-ESO-1 tumor antigen recognition by CD4+ effector T cells. OncoImmunology (2018) : HAL INSERM 01644345
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 (2017) : HAL INSERM 01480165
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) : HAL INSERM 01386814
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) : HAL INSERM 01299450
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. Oncotarget (2015) : HAL INSERM 01285131