Altering the Vasculature to Promote Tumour Immunity

The journal Science voted “Cancer Immunotherapy” the most important scientific breakthrough in 2013 due in part to the success of adoptive T cell therapy. However, the success of this treatment and others may be limited by the failure of activated lymphocytes to effectively infiltrate tumors. Using an established mouse model where carcinogen-induced tumours arise in vivo, we have reported that depletion of Foxp3+ regulatory T cells (Tregs), can promote development of specialised blood vessels (high endothelial venules or HEV) in tumours. HEV are normally found only in secondary lymphoid tissue where they facilitate transit of naïve and central memory T cells into the lymph node parenchyma. However, in a recent study HEV have been detected in breast tumours where a significant association between HEV presence and density of tumour-infiltrating lymphocytes (TIL) was observed. Significantly a correlation between the presence of HEV and a favourable prognosis in breast cancer and melanoma patients was reported. In our mouse model of tumorigenesis we also found that the presence of intra-tumoural HEV correlated with a significant increase in the number of TIL and control of tumour growth. Thus, the main objectives of our current work are to determine how HEVs are induced in tumours and the role Tregs play in this process and to test novel immunotherapeutic approaches to drive intra-tumoural HEV neogenesis using established pre-clinical mouse models of cancer. The overall aim is to devise new treatments, combining immunotherapy with regimes designed to alter the tumour vasculature.