Complex brain organoid model reproducing the glioblastoma tumor niche and its immune component for the development of personalized medicine

Glioblastoma, responsible for 3,500 annual deaths in France, is an extremely aggressive brain tumor that is resistant to current treatments. Clinical trials in immunotherapy have shown only transient effects, underscoring the importance of understanding resistance mechanisms and developing more targeted therapeutic strategies.

We have developed an innovative model of glioma stem cell invasion in immunocompetent and vascularized brain organoids derived from induced pluripotent stem cells (iPSCs) (Raguin et al., submitted). This model faithfully reproduces the glioblastoma tumor niche, including vascular co-option, reprogramming of microglia into tumor-associated macrophages, and tumor recurrence following radiotherapy.

The aim of this PhD project is to derive a universal brain organoid model for the transfer of glioma cells from patients and lymphocytes to optimize the immunotherapy approach (CAR-T cells).

The project involves creating a universal model of human brain organoids that are immunologically "silent" by suppressing the expression of the HLA class I/II system in iPSCs (CRISPR/CAS9 for the ß2M and CIITA genes). Additionally, it aims to elucidate the mechanisms of immunosuppression induced by irradiation, such as the reprogramming of microglial/macrophage cells and the involvement of senescence. Various approaches to make the tumor microenvironment more conducive to immunotherapy will be explored, including activating the type I interferon pathway through genetic modification or with cGAS/STING pathway agonists. Subsequently, the use of CAR-T cells targeting an antigen overexpressed by glioblastoma cells (CD276/B7-H3) will be studied. This model could be used in personalized medicine by co-cultivating patients' tumor cells, monocytes, and CAR-T cells.

This project offers innovative perspectives for the personalized treatment of glioblastoma via immunotherapy and could represent a major advancement in this therapeutic approach.

Multiplexed whole-body in vivo imaging monitoring of pathogen dissemination and immune responses dynamics in tuberculosis

This thesis is dedicated to set up a multiplexed medical imaging monitoring of pathogen colonization and associated immune responses dynamics at the whole body scale for various infectious diseases. This could provide an innovative and non-invasive tool to better understand dynamics links between immune responses and pathogen distribution throughout the body and potentially provide new biomarkers associated to several diseases. To tackle this issue this thesis would implement such strategy in tuberculosis disease. The main aim is to determine the relationship between Mycobacterium tuberculosis dissemination and associated immune responses across the whole body during the course of tuberculosis infection from early infection to latent or active tuberculosis thanks to innovative multiplexed imaging protocols. The goal of this study is to provide correlations in time and space between local bacterial burden and several immune cell infiltrations (activated macrophages and T lymphocytes subsets) occurring following infection and detected over time by imaging. These findings could then provide, with minimal invasiveness, predictive biomarkers on disease or local granuloma progression and may provide also valuable insight on potential immune targets for future preventive or curative strategies based on modulation of the immune system. To do so, this thesis would take advantage of the preclinical Non-human primate model of tuberculosis developed in France and on our in vivo imaging of pathogens and immune cells expertise in NHPs. Of note, deeper immune cell profiling in samples of interest (imaging guided) will be assessed by spatial or single-cell transcripomic technologies in tissue samples to provide additional readouts on TB pathophysiology and potential treatment efficacy.

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