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L'absence de CD226 caractérise des LT CD8+ hyporépondeurs au TCR et aux fonctions antitumorales défectueuses

Abstract : CD8+ cytotoxic T lymphocytes (CTL) are key immune cells that play an important role in the control of tumor development through their ability of killing cancer cells. However, cancer cells can frequently escape CD8 T-cell recognition and cytolytic functions through the engagement of inhibitory receptors such as CTLA-4 and PD-1. Although immune checkpoint blockade (ICB) such as monoclonal antibody (mAb) anti-PD-1 has represented a promising cancer therapy in cancer care, clinical responses are not observed in the majority of cancer patients. Therefore, elucidating the mechanisms of this lack of responsiveness and finding additional signals that regulate CD8+ T cell anti-tumor functions has become a major priority. While most of the experimental strategy mainly focus on the identification of additional inhibitory receptors, the importance of coactivating receptors in the antitumor CD8+ T cell functions and ICB efficacy remains to be better investigated. Initially described as an adhesion molecule, CD226 (DNAM-1) is co-activating receptor expressed by NK cells and CD8+ T cells that stimulate the secretion of pro-inflammatory cytokines and release of cytolytic granules towards target cells. Its ligands, the nectin and nectin-like receptors CD112 and CD155, are often expressed on cancer cells and CD226 was shown to play a critical role in immunosurveillance in numerous tumor mouse models. The inhibitory receptors TIGIT and CD96 that compete with CD226 were recently identified as promising immunotherapeutic targets to restore CD8+ T cell reactivity against cancer, thus highlighting the importance of CD226 axis in the regulation of anti-tumor immune responses. During my PhD, I found that CD226 identifies CD226- CD8+ and CD226+ CD8+ T cells populations in healthy donors and in cancers patients. Through transcriptomic, molecular and functional analysis, I found that the CD226 absence alters CD8+ T cell responsiveness to TCR stimulation. Unlike CD226+ CD8+ T cells, CD226- CD8+ T cells have deeply intrinsic functional abnormalities such as poor proliferation, cytokines production and cytotoxic functions upon TCR stimulation. Using complementary set of experiments involving human samples and mouse tumors models, I observed that tumor development favors the accumulation of tumor-infiltrating CD226- CD8+ T lymphocytes (TILs) through an Eomes-dependent mechanism.[...]
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Marianne Weulersse. L'absence de CD226 caractérise des LT CD8+ hyporépondeurs au TCR et aux fonctions antitumorales défectueuses. Immunologie. Université Paul Sabatier - Toulouse III, 2019. Français. ⟨NNT : 2019TOU30174⟩. ⟨tel-02948443⟩

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