ANEMONE The ANswer within the microEnvironment: Malignant pleural mesothelioma resistance to Old and NEw drugs

Pleural mesothelioma (PM) is a rare malignant intrathoracic tumor with a very poor prognosis. The most important cause is asbestos exposure. As PM typically takes 20 to 50 years to develop after exposure, the incidence is expected to increase , reaching a peak around 2025. Asbestos fibers lead to a protracted immune response, however, to date a clear relationship with the response to treatment with immunotherapy has not been found. The main aim of this project is to characterize the tumor microenvironment using genetic analyses to identify gene-immune environment interaction and mechanisms that could explain the functions of tumor-infiltrative immune cells. Furthermore, it will explore radiologic phenotyping using a radiomic approach to assess the immune microenvironment. The hypothesis is that crucial components of the tumor microenvironment could support the survival of malignant mesothelial cells and escape from immunosurveillance and their destruction. This project brings together experts in pathology, molecular biology, bioinformatics , and radiology who are essential to make a significant step forward in the knowledge about PM microenvironment. It is planned to analyze pleural biopsies of 360 chemo nave PM patients (300 retrospective and 60 prospective), recruited from Padova, Pisa, Graz, Coimbra, and Riga from 2018 to the end of 2023. A subset of epithelioid PM surgically treated will be investigated before and after chemotherapy treatment. Radiomics applied to computed tomography scans will be performed in all cases. Additionally, tumor microenvironment cells will be evaluated using multiplex immunofluorescence, image analysis, and Artificial Intelligence. In a subset of cases whole genome sequencing, RNA sequencing, and proteomic analyses will be conducted. Identified potentially therapy-relevant pathways in clinical samples will be further investigated using in vitro (primary PM cell cultures) and in vivo (murine) models. It is expected that this interdisciplinary approach will lead to the identification of key pathways and crucial markers in the tumor microenvironment which will enable better management of PM. Results should have a strong impact on PM patients identifying categories who will benefit more from the selected treatment, thus improving the life expectancy, and efficiency of the healthcare system and driving down healthcare costs.