Thesis, COLLÉGIALITÉ

Abstract

Malignant Pleural Mesothelioma is an aggressive tumor arising from the pleura. The World Health Organization reported 30,870 new cases and 26,278 deaths in 2020, highlighting the extremely high mortality rate of this malignancy. The overall survival varies from 9 to 15 months depending on the histological subtype, the stage, and the treatment. For more than a decade, a combination of two chemotherapeutic agents (pemetrexed plus cisplatin) was the standard-of-care for malignant pleural mesothelioma. However, the survival remained poor (~12 months). Interestingly, in 2021, the Food and Drug Administration approved a combination of ipilimumab plus nivolumab for the treatment of this cancer, showing the benefit of immunotherapy in this context. The purpose of this present master thesis was the characterization of the immune checkpoint profile of pleural mesothelioma as well as of their immune microenvironment. Bioinformatic analyses, immunohistochemistry, western blot, and syngeneic models were performed/used to correctly characterize and select promising targets for further investigations. Collectively, in this project, we highlighted VISTA, CD200 and CD47 as potential promising targets which could be blocked by inhibitors (e.g. monoclonal antibodies). These data provide strong evidence for further exploring these “second-generation” immune checkpoints as potential novel immunotherapeutic targets in the context of malignant pleural mesothelioma.