Nicolas Boisgerault

Live-attenuated measles virus (MV) infects cancer cells through the CD46 receptor, commonly overexpressed in tumors, and replicates preferentially in cells with impaired type I interferon (IFN-I) response. To enhance immune stimulation, we engineered a C protein–deficient MV (MVdeltaC), thus eliminating a key viral antagonist of innate immunity. MVdeltaC exhibited potent oncolytic activity in a broad panel of human tumor cell lines, with a vast majority of them showing high sensitivity. This enhanced efficacy is dependent on RIG-I stimulation, mainly through the generation of defective viral genomes, which trigger apoptosis, robust IFN-I signaling and massive CXCL10 production. MVdeltaC infection induced immunogenic cell death, the release of danger signals, and the maturation of dendritic cells. In vivo, MVdeltaC significantly reduced tumor burden in xenografts and patient-derived xenograft (PDX) models. Intratumoral MVdeltaC administration in immunocompetent A/J mice grafted with syngeneic neuroblastoma led to complete tumor rejection in 90% of animals and long-term antitumor memory. Efficacy was dependent on CD8+ T and NK cells and was further enhanced by anti- CTLA-4 treatment or CD4+ T cell depletion. Prior measles immunization accelerated tumor clearance, indicating memory-boosted antitumor responses. These findings support the clinical potential of MVdeltaC as a strong RIG-I activator for next-generation large-spectrum anticancer therapy.

Background: As a complement to the clinical development of new anticancer molecules, innovations in therapeutic vectorization aim at solving issues related to tumor specificity and associated toxicities. Nanomedicine is a rapidly evolving field that offers various solutions to increase clinical efficacy and safety. Main: Here are presented the recent advances for different types of nanovectors of chemical and biological nature, to identify the best suited for translational research projects. These nanovectors include different types of chemically engineered nanoparticles that now come in many different flavors of ‘smart’ drug delivery systems. Alternatives with enhanced biocompatibility and a better adaptability to new types of therapeutic molecules are the cell-derived extracellular vesicles and micro-organism-derived oncolytic viruses, virus-like particles and bacterial minicells. In the first part of the review, we describe their main physical, chemical and biological properties and their potential for personalized modifications. The second part focuses on presenting the recent literature on the use of the different families of nanovectors to deliver anticancer molecules for chemotherapy, radiotherapy, nucleic acid-based therapy, modulation of the tumor microenvironment and immunotherapy. Conclusion: This review will help the readers to better appreciate the complexity of available nanovectors and to identify the most fitting “type” for efficient and specific delivery of diverse anticancer therapies.

Médecine/sciences (M/S), revue internationale dans le domaine de la recherche biologique, médicale et en santé

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The tumor microenvironment content, particularly the presence of macrophages, was described as crucial for the development of the disease. This work aimed at studying the involvement of the M-CSF (CSF-1)/IL-34/CSF-1R pathway in the formation of macrophages in MPM, using samples from patients. Methods: Pleural effusions (PEs), frozen tumors, primary MPM cells and MPM cell lines used in this study belong to biocollections associated with clinical databases. Cytokine expressions were studied using real-time PCR and ELISA. The Cancer Genome Atlas database was used to confirm our results on an independent cohort. An original three-dimensional (3D) coculture model including MPM cells, monocytes from healthy donors and a tumor antigen-specific cytotoxic CD8 T cell clone was used. Results: We observed that high interleukin (IL)-34 levels in PE were significantly associated with a shorter survival of patients. In tumors, expression of CSF1 was correlated with ‘M2-like macrophages’ markers, whereas this was not the case with IL34 expression, suggesting two distinct modes of action of these cytokines. Expression of IL34 was higher in MPM cells compared with primary mesothelial cells. Particularly, high expression of IL34 was observed in MPM cells with an alteration of CDKN2A. Finally, using 3D coculture model, we demonstrated the direct involvement of MPM cells in the formation of immunosuppressive macrophages, through activation of the colony stimulating factor-1 receptor (CSF1-R) pathway, causing the inhibition of cytotoxicity of tumor antigen-specific CD8⁺ T cells. Conclusions: The M-CSF/IL-34/CSF-1R pathway seems strongly implicated in MPM and could constitute a therapeutic target to act on immunosuppression and to support immunotherapeutic strategies.

Oncolytic 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).

Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma