Conventional cancer therapies such as chemotherapy and radiation often lead to severe side effects since they are unable to specifically target the tumor. Additionally, they do not guarantee the prevention of metastasis or recurrence. Recent developments on small-molecule inhibitors, such as kinase inhibitors that target cellular pathways characteristically upregulated in cancer cells, show promise. However, significant challenges such as tolerance and mutations causing drug resistance need to be overcome. Immunotherapy, wherein the host's immune system is leveraged to recognize and target cancer cells, is a better alternative that shows reduced toxicity. Macrophages are an attractive target for immunotherapy seeing as they constitute 50% of the infiltrating leukocytes in the tumor microenvironment. Their plastic nature allows them to be modulated from pro-tumor to anti-tumor phenotype. Although, it does not work for everyone, necessitating a need to monitor response to medication at earlier time points. In this thesis, I have designed an HDL mimicking nanoparticle system to target tumor associated M2 macrophages through the SRB1 receptor. The nanoparticle was optimized for better stability, better loading of the targeting peptide, and the drug as well. It was used to deliver a CSF1R inhibitor drug to successfully repolarize pro-tumor M2 macrophages to anti-tumor M1 phenotype. In addition to that, it was also used to deliver an Arginase-responsive probe that only fluoresces when engulfed by arginase-producing M2 macrophages, differentiating them from arginase non-producing M1 phenotype. Through this study, the SRB1 receptor was successfully targeted to effectively deliver small molecules. This can be used to target and modulate tumor-associated macrophages.

No description available.

Le VHC est une cause majeure de cancer du foie. Le traitement actuel est caractérisé par à un cout élevé, la présence de toxicité et l’émergence de résistance virale. Dans la 1ère partie de ma thèse, je me suis intéressé à l’entrée virale. L’entrée est nécessaire pour l’initiation ; la dissémination et le maintien de l’infection et représente ainsi une cible intéressante dans le développement de thérapies antivirales : CD81 et SRBI sont les 1ers facteurs décrits comme importants pour l’entrée : Nous avons confirmé leur rôle clé dans l’entrée et les étapes suivant l’entrée. De plus, nous avons montré leur rôle crucial dans la transmission cellule/cellule. Le VHC infecte principalement les hépatocytes, nous avons étudié en seconde partie de ma thèse le tropisme restreint du VHC aux hépatocytes. En définissant les facteurs essentiels à l’infection de cellules non hépatiques et en développant un modèle cellulaire afin d’identifier de nouveaux facteurs d’assemblage et de réplication du VHC. / HCV infection is the leading cause of chronic liver disease. The current SOC is still limited by high costs, toxicity and emergence of viral resistance. In the first part of my thesis we focused our workon viral entry. Viral entry is required for initiation, spread, and maintenance of infection, and thus is a promising target for the development of new antiviral therapies. CD81 and SR-BI are the first entry factors identified as important for HCV entry. In our work we confirmed their crucial role in entry, especially at the post-binding step. In addition we proved their key role in viral dissemination through the cell-cell transmission. As HCV mainly infects hepatocytes, we studied in the second part of my thesis, the restricted cellular tropism of HCV to hepatocytes and we defined the minimal host factors rendering non hepatic cell lines susceptible to HCV infection by the establishment of a powerful tool to identify new assembly and replication factors.