Dr. Thorsten Hagemann

Research Institution:Centre for Cancer and Inflammation, Barts Cancer Institute

Award: £150,000 Duration: 3 years

Project Title: Enhancing oncolytic adenovirus efficacy in pancreatic cancer by switching tumour-associated macrophages

Research Aims:The pivotal role of tumour-associated macrophages (TAMs) in tumour progression is now well established. TAMs have been shown to influence multiple steps in tumour development including the growth, survival, invasion and metastasis as well as angiogenesis and lymphangiogenesis. The molecular circuits which polarise TAMs towards such a protumoral phenotype are now the focus of intense investigation. We propose that targeting specifically TAMs and their phenotype can increase protective immunity in experimental models of  cancer and complement therapies such as oncolytic adenoviruses.

Most human and experimental cancers have a large tumour-associated Mφ (TAM) population but the tumour microenvironment promotes an M2 phenotype and inhibits this anti-tumour potential. The adaptive immune system has the potential to recognise and eliminate malignant cells; in experimental models of cancer the adaptive immune system can limit growth of spontaneous and transplanted tumours and Ag-specific T cells can be detected in human cancers, but the tumour microenvironment acts as a barrier for the development of protective immunity. Non-specific 'innate' tolerance can be maintained by innate immune cells through the production of anti-inflammatory and immunosuppressive mediators and down-regulation of APC activity. In the experiments outlined in this proposal we will explore the hypothesis that the macrophage phenotype in the tumour micronevironment compromises oncolytic adenovirus efficacy. We hypothesise that targeting the macrophage infiltrate within the tumour microenvironment will enhance the adenoviral therapy and improve tumour killing. The project has the potential for identification of a novel point of therapeutic intervention.