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Theses

La souris humanisée : modèle d'étude de l'immunothérapie anti-cancer

Abstract : Immunotherapy is revolutionizing cancer treatment by shifting the treatment strategy from targeting the tumor to targeting the immune system. The blockade of immune checkpoints with anti-CTLA-4, anti-PD1 and anti-PD-L1 antibodies shows impressive clinical results. However, the response rate remains low. It is therefore essential to better understand the mechanisms of action of these therapies, to identify biomarkers of response and toxicity, and to evaluate therapeutic combinations. Such mechanistic and preclinical studies require the optimization of adapted murine models. For these purposes, my PhD work has focused on the development of humanized mouse models, in which immunodeficient mice are grafted with human tumor (cell lines or patient derived xenografts) and immune cells to study different immunotherapy approaches. In humanized mouse models, the human immune cell compartment can be reconstituted from either hematopoietic stem cells (HSC) from umbilical cord blood or with mononuclear cells from human blood (PBMC). We have observed that the injection of HSCs generates several subpopulations of immune cells (myeloid cells, T and B lymphocytes, NK cells), detectable from 4 weeks; while the injection of PBMCs mainly generates T lymphocytes, detectable from 1 week. In the latter model, lymphocyte reconstitution is associated with an anti-tumor effect, but is also accompanied by the development of graft-versus-host disease. Both models have advantages and disadvantages for the evaluation of cancer immunotherapies, which are discussed in my thesis. Using these models, we evaluated the therapeutic effect of a clinically used anti-PD1 antibody on tumor cell lines or on patient derived xenografts of different types of tumors. We observed a heterogeneity in the response to treatment, reflecting the clinical observation of responder and non-responder patients. Finally, in order to evaluate the interest of humanized mice for the study of therapeutic combinations, we tested an anti-PD1 therapy associated with a targeted therapy in bladder cancer. Our results, identifying the strengths and limitations of humanized mice, demonstrate the relevance of these new models for the evaluation of immuno-oncology therapies and open perspectives in the study of therapeutic combinations.
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Philippe De La Rochère. La souris humanisée : modèle d'étude de l'immunothérapie anti-cancer. Immunologie. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB068⟩. ⟨tel-02510742⟩

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