Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy

Abstract

The formation of new blood vessels — known as angiogenesis — is essential for the growth and spread of solid tumours. It is promoted by the hypoxic conditions that develop in growing tumours and drive the expression of pro-angiogenic growth factors by tumour cells and various stromal cells. However, the tumour-associated vasculature (TAV) generated by angiogenesis is abnormal and is a key barrier to T cell entry into tumours. Moreover, the TAV creates a hostile microenvironment owing to an accumulation of suppressive immune cells, hypoxic and acidic conditions, and high interstitial pressure, which all limit the function and survival of effector T cells. Here, we present the mechanisms of T cell migration into tumours, including via high endothelial venules, and the importance of tertiary lymphoid structures, which function as privileged sites for antigen presentation, activation and co-stimulation of T cells, for mounting effective antitumour immunity. We describe how the tumour vasculature limits antitumour T cell responses and how T cell responses could be improved by therapeutic targeting of the TAV. In particular, the use of combination therapies that aim to normalize tumour blood vessels, favourably reprogramme endogenous immunity, and support T cell trafficking, function and persistence will be key to improving clinical responses.