6533b86efe1ef96bd12cba3e

RESEARCH PRODUCT

Identification of non-canonical NLRP3 functions in Th17 cells - Therapeutic interest to promote antitumor immune response

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Since decades, cancers have become a major public health issue, occupying the first premature mortality cause in France. One of the hallmarks of cancer cells is their ability to escape the immune system surveillance, notably through setting up an immunosuppressive environment within the tumor. The NLRP3 protein is largely studied in the inflammasome context, which is assembled in order to promote inflammation through IL-1β secretion. However, this protein also functions as a transcription factor in CD4+ T cells. Indeed, in Th2 cells, NLRP3 cooperate together with IRF4, to form a complex that is able to activate the transcription of Il4, Il5 and Il13, which are necessary for the function of Th2 cells.This work is focusing on Th17 cells, a CD4+ T cell population of which there are different subtypes with different functions. Among these subtypes, two are opposite in the context of cancer, inflammatory Th17 (Th17i) which has antitumor properties, and regulatory Th17 (Th17r) which has pro-tumor properties.The work achieved during this thesis allowed showing that NLRP3 participate to Th17i / Th17r balance. Indeed, NLRP3 deficiency limit the emergence of a Th17r profile in favor of a Th17i-like profile, with the increase in the expression of Th17i characteristic inflammatory cytokines such as IFNγ, GM-CSF or IL-21. This gives to Th17 the ability to stimulate CD8+ T cells to increase their IFNγ and Granzyme B secretion. Although the interaction between NLRP3 and IRF4 exist in the nucleus of Th17r, another NLRP3 function modulate the expression of genes responsible for the phenotypic switch. Indeed, NLRP3 participate to repression of key genes of the Th17i transcriptional program, notably through facilitating SMAD3 phosphorylation. These phenomenon translate into an antitumor activity, which result in a decrease in tumor development in vivo. Consistently, the immune infiltrate of B16-F10 and LLC1 cancer cell line from CD4crexNLRP3flox mice or Th17rOT-II Nlrp3-/- transferred B16-F10OVA bearing mice, are enriched in CD8+ T cells which show greater cytotoxicity and a decrease in TReg infiltrate, resulting in a decrease in the immunosuppression within the tumor.To summarize, this work allowed to identify NLRP3 as a key factor in Th17r polarization, and highlighted its role in Th17r immunosuppressive functions acquisition.