Using_murine_models_of_malignant_mesothelioma_to_understand_clinical_immune_responses

Aim: To sequence the exome of murine mesothelioma models, characterise the genetic alterations that have occurred comparing both germline and tumour DNA, and identify non-synonymous mutations that generate new MHC restricted epitopes. This will enable us to follow the background immune response (CD8 T cells) and how they change with tumour progression and how chemotherapies and immunotherapies alter these responses. This will provide the basis for examining the immunogenicity and specificity of mutant epitopes in patients with the prospect of improved immunotherapy for these patients. Background: Malignant mesothelioma is an aggressive tumour of the serosal cavities, most commonly of the pleura. Diagnosis is difficult (Addis and Roche 2009), treatment options limited (Bagia and Nowak 2011) and median survival of patients receiving best available care is 12 months (Vogelzang, Rusthoven et al. 2003)(Edwards, Abrams et al. 2000) with all patients eventually succumbing to the disease. Mesothelioma was once considered rare but now kills around 15,000 people per annum world-wide. We use murine models of asbestos-induced mesothelioma to explore the biological, including immunological, pathogenesis of mesothelioma and to assess different treatment approaches. We have developed several different murine model systems all of which are similar to the human counterpart exhibiting similar pathology and gene expression profiles; furthermore they are induced by the same carcinogen (Robinson, Walsh et al. 2011). We have used these systems to further our understanding of immunological cross presentation in tumours (Marzo, Lake et al. 1999; McDonnell, Prosser et al. 2010) and have develop immunotherapy protocols which we are currently trialling in patients. The effectiveness of this program of work would be enhanced by a greater understanding of the tumour antigens present in these models. In this project, we will sequence the exome of our murine mesothelioma models and characterise the genetic alterations that have occurred, comparing both germline and tumour DNA, and DNA from tumour lines transfected with various proteins. By identifying non-synonymous mutations will be able to evaluate the immunogenicity and specificity of mutant epitopes by immunizing mice with synthetic peptides.