Tumour immune microenvironment, genomewide copy number aberrations and their interactions in malignant pleural mesothelioma

© 2017 Dr. Bibhusal ThapaMalignant pleural mesothelioma (MPM) is a rare but deadly malignancy. Despite predictions, worldwide incidences have not significantly diminished and available therapeutic modalities have failed to improve outcomes. There are some indications that immune based therapies and targeted therapies may hold promise but suitable phenotypes have been hard to identify. This thesis describes investigations we conducted into the tumour immune microenvironment, the copy number aberrations (CNAs) and the interaction between the two in MPM. The findings presented in this thesis elucidate the complexity of the tumour immune microenvironment in MPM. We establish MPM to be immunogenic but also demonstrate that the immune characteristics vary amongst tumours mostly with tumour histological subtype. We reveal sarcomatoid MPMs to be associated with high lymphocytic infiltration but also greater expression of immune checkpoint receptors and their ligands. In addition, we also exhibit the prognostic implications associated with some of these markers. The genome wide copy number analyses described in this thesis disclose that although copy number aberrations are the commoner of genomic alterations in MPM, their extent and pattern vary amongst tumours. We describe their clinical and pathological associations. We confirm most previously described prominent CNAs but more importantly uncover new ones which may be important in MPM prognostication and therapeutics. We find that greater degree of genomic instability confers a worse prognosis in MPM independent of histology but neither degree of genomic instability nor any specific CNA correlates with the immunological milieu. Our findings contribute towards the understanding and development of potential prognostic and predictive markers for immunotherapy in MPM. Further, they also reveal potential targets for development of targeted therapies in this disease where none was thought feasible