Travail de fin d'études: Chemotherapy-mediated activation of DNA damage tolerance pathways to improve immunotherapy in pleural mesothelioma

Abstract

Pleural mesothelioma is a rare and aggressive tumour originating from mesothelial cells of the pleura. For a long time, chemotherapy, sometimes combined with surgery and radiotherapy, has been the primary treatment option, though not definitively curative. Advances in immunotherapy have been and are being pursued. Particularly, one treatment involving the combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) has shown promising results in phases II and III of clinical trials. Moreover, this treatment has shown higher effectiveness in the presence of neoantigens. In this context, the aim of this master thesis is to use low-dose of chemotherapeutic agents to potentially generate neoantigens through DNA damage leading to mutations. This work highlighted that three chemotherapeutic treatments out of the five tested, namely the combination of cisplatin with pemetrexed, doxorubicin, and cyclophosphamide, could be good candidates. These exhibit a range of promising traits including a lack of substantial impact on cellular metabolism and apoptosis, induction of DNA damage, activation of repair and tolerance mechanisms for these impairments, increase of MHC-I expression, and enhancement of immune responses orchestrated by macrophages.