Activation of DNA damage tolerance pathways to improve immunotherapy treatment in malignant mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that affects the mesothelial cells of the pleura. Conventional treatments include surgery, radiation therapy and chemotherapy. In the vast majority of cases, none of these treatments is definitively curative. In this context, new approaches such as immunotherapy show promise. In particular, a treatment targeting the immune checkpoint inhibitors PD-1 and CTLA4 (nivolumab and ipilimumab, respectively) is effective against the sarcomatoid subtype of MPM. Furthermore, a positive correlation links the efficacy of PD-1 and CTLA4 immunotherapy with the presence of neoantigens. In this context, the aim of this master thesis is to use chemotherapy at sublethal doses to induce DNA damage and create new mutations potentially generating neoantigens. This work identified doxorubicin among a series of 7 preselected compounds, as a candidate exhibiting the targeted characteristics, namely: the absence of a significant effect on cell metabolism and apoptosis, induction of DNA damage, the initiation of repair and tolerance mechanisms to these lesions and improvement of the immune response directed by macrophages.