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RESEARCH PRODUCT

Etude de NLRP3 dans les cellules myéloïdes immunosuppressives et les lymphocytes TCD4 dans un contexte de cancer

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The inflammasome NLRP3 (NOD like receptor pyd containing 3) is a multiprotein complex notably responsible for IL-1β (interleukine-1β) production, an inflammatory cytokine. Negative effects have been observed in various diseases including cancer. My thesis focuses on the effects of NLRP3 in cancer.In my first project, I studied the NLRP3 inflammasome activation in MDSC (myeloïd derived suppressor cells) after a chemotherapy treatment. Two chemotherapies, 5-Fluorouracil and Gemcitabine, are selectively able to kill MDSC, an immunosuppressive population growing during cancer evolution. MDSC’s death restores anti-tumor immunity for a while but another immunosuppressive population is established by MDSC produced IL-1β before their disappearance. I discovered that 5-Fluorouracil and Gemcitabine trigger NLRP3 inflammasome activation in MDSC. 5-Fluorouracil and Gemcitabine induce lysosomal permeabilisation, allowing for Cathepsin B release into the cytoplasm where it directly interacts with NLRP3. That interaction activates the inflammasome and induces IL-1β production which is responsible for the development of another immunosuppressive population, called Th17 cells.I then studied the role of NLRP3 during Th2 differentiation. Here, NLRP3 actions are done independently of the other inflammasome forming proteins. After being induced by IL-2 signalization pathway, NLRP3 interacts with IRF4 (interferon regulatory factor 4) and acts as a transcription factor on the IL-4 promoter gene. Lack of NLRP3 leads to a smaller IL-4 production by Th2 cells which are consequently less functional