Description du sujet de thèse

-------- Glioblastomas (GBM) are the most aggressive brain tumors and are resistant to immunotherapies due to their immunosuppressive environment, primarily driven by tumor-associated macrophages (TAMs). TAMs are the predominant immune cells in GBM and consist of various subsets that can be either anti- or pro-tumoral, yet the specific roles of each subset remain unclear. Correlating TAM phenotype with function is essential for developing effective future treatments. We have identified the ML-IAP protein, associated with poor GBM outcomes, in specific TAM subsets. Using an ML-IAP inhibitor, we demonstrated that these TAMs can be shifted to an anti-tumor state. The goal of this project is to understand the specific roles of each ML-IAP TAM subset by creating new ML-IAP inhibitors for precise targeting, utilizing cutting-edge imaging techniques and bioorthogonal methods. This project is feasible due to the collaboration between biologists and chemists, which will facilitate the development of innovative therapeutic strategies.

Contexte de travail

Glioblastoma (GBM) is a severe brain tumor with limited treatment options(1). Standard care involves surgery, radiotherapy, and chemotherapy with temozolomide, but the tumor's aggressive nature leads to recurrence and a low 5-year survival rate of less than 10%. The median survival is only 15 months post-diagnosis, partly due to an immunosuppressive environment dominated by tumor-associated macrophages (TAMs). While immunotherapies have improved outcomes for other cancers, they have not been effective for GBM(2), likely due to the presence of immunosuppressive TAMs(3). Targeting these TAMs to reverse immunosuppression is a promising strategy, but their functions are diverse and not well understood. The CAMEL project aims to characterize a specific TAM subset, ML-IAP+ TAMs, to better understand their role and propose new therapeutic strategies to enhance treatment efficacy.

Contraintes et risques

The project will be in collaboration between 2 laboratories, one of biology and the other one of chemistry. This interdisciplinarity is the fondation of this project.