Owing to an increased appreciation of the potential for immunotherapy in neoplasia, much attention has been focuing on a greater understanding of the immune, bidirectional intricacies involving the Tumor MicroEnvironment (TME). Recent work has demonstrated that TME elicits environmental changes, metabolic in nature, in the host’s immune cells, that dampen their ability to REACT against tumors. Manipulating the biology of oncometabolites can strengthen an antitumor immune response as well as circumvent therapy resistance. Here I propose innovative modalities to tackle this problem. The Aryl hydrocarbon Receptor (AhR), best known as the receptor for dioxins, has recently been shown to be one "central node" for communication between host's cells and its ligands, disparate as the nature and source. I have recently found that selective AhR deletion in a subset of antigen presenting cells triggers the rejection of an otherwise progressive fibrosarcoma tumor in vivo. I thus hypothesize that, AhR, expressed in orchestrators of immune responsiveness, represents a key sensor of TME composition, influencing the outcome of an immune reaction against tumors. The main objective of this project is to identify AhR-activating metabolites in TME and disclose their impact on tumor rejection or progression. In parallel, I aim at developing novel advanced strategies, with a high degree of translatability to human cells, to specifically inhibit AhR or AhR-dependent programs in selected APCs. I will combine state-of-the-art technology with new and powerful technologies, including advanced single-cell analysis, promoter gene-editing approaches and computational chemistry. The potential of such a project is very high, because such metabolites may be predictors of immune activation or suppression in TME, and the downstream targets of those immunesuppressive oncometabiltes may represent druggable targets to inhibit tumor escape mechanisms.
Multiple sclerosis (MS) is a chronic and progressive neurodegenerative disease that is currently affecting 2.3 million people worldwide. Incidence rates of MS are significantly higher in Europe and in other regions located within the northern hemisphere. In Europe, the number of patients currently afflicted with MS is estimated to be at 700,000, with incidence rates ranging from 2.3-12.2/100,000 per year. GlobalData assessed the market value for MS treatments in 10 major markets (France, Germany, Italy, Spain, UK, US, Canada, Japan, China and India) in 2014 to be at €16.2 billion and predicts it to rise to approximately €18.82 billion by 2024. This increase is attributed to the projected sales of newly-approved drugs. The main shortcoming of current MS treatments ultimately lies in their lack of efficacy, specifically in that they are unable to prevent progressive neurodegeneration in MS patients. MS poses a significant economic burden on society as the disease affects primarily young people who are in their most economically-productive years. Aside from limited efficacies, current treatment options are also associated with severe side-effects (increased risks of infection, cancer), high costs and inconvenient administration routes (e.g. intravenous, intramuscular, subcutaneous). The aim of DIDO-MS is to assess the commercial viability of a newly identified small molecule as a drug in the treatment of MS.
Invasive alien herbivore species are a major threat to agriculture because they directly damage crops and induce severe yield losses, but also because they indirectly impact the structure, stability and functioning of native arthropod communities. Indirect facilitation mechanisms can cause unpredictable outbreaks of native pest species but, surprisingly, they have been rarely studied within arthropod communities. Within the framework of invasive species management (Regulation EU 1143/2014), understanding pest facilitation mechanisms is a research priority. This is also because invasive species negatively impact the reliability of agricultural Decision Support Systems, used in sustainable agriculture (Directive 2009/128/EC). PESTNET aims, as general objective, at developing a novel inter- multidisciplinary and intersectoral approach (field monitoring, DNA metabarcoding, multilayer ecological network analyses, citizen science) to depict the basic and applied ecological consequences of a human-introduced alien crop pest on the invaded trophic network. The model system used for implementation is represented by the highly invasive Brown Marmorated Stink Bug, Halyomorpha halys, native stink bug species and shared egg parasitoids. An original two-fold cutting-edge approach is proposed aiming at assessing the following specific objectives: Obj. 1) Evaluation of indirect pest facilitation mediated by host-parasitoid prevalence in non-invaded vs. invaded networks; Obj. 2) Evaluation of stink bug community changes using a mobile monitoring system (app) to estimate spatial trends in stink bugs abundance. Through the involvement of academic and non academic (industry) partners, the project will provide novel insights on how an invasive herbivore pest of worldwide economic importance is impacting sustainable agriculture by interference with the local arthropod community.