Development of Cytomegalovirus-Based Vectors in Cancer Vaccination

The immune system can eliminate tumour cells, yet such anti-tumour immunity is largely suppressed in the tumour microenvironment. Here we will use in vivo imaging in combination with genetic manipulation to understand and overcome limitations in how immune cells access a tumour, regulate tumour vascularisation and kill tumour target cells.

The immune system with CTLs as its central cytolytic effectors can eliminate tumour cells, yet such anti-tumour immunity is largely suppressed in the tumour microenvironment. Overcoming such tumour immune suppression has great therapeutic potential.

Effective immune cell extravasation occurs in specialized blood vessels, high endothelial venules (HEV). Using fixed tumour sections the Gallimore laboratory has found that initial extravasation of immune cells including T cells into the tumour induces HEV in the tumour. This enhances further extravasation in a feed-forward-loop. Importantly, Treg suppress HEV induction.

Studying tumour CTLs ex vivo the Wuelfing laboratory found that tumour CTLs readily bind to tumour cells but fail to sustain these contacts as required for effective killing. Importantly, engagement of inhibitory receptors on CTLs (prominently PD-1 and Tim-3) by tumour-expressed ligands suppresses tumour cell killing. Thus we hypothesise that tumour immune suppression involves two sequential steps, suppression of CTL access to and activation within the tumour by Tregs and suppression of CTL killing by inhibitory receptors. Cross-regulating effects of Tregs on cytolysis and inhibitory receptors in local T cell activation are likely, necessitating an integrated experimental approach.

To test this hypothesis with greatest physiological relevance, we will investigate the relevant cellular interactions inside tumours in live animals combining two-photon microscopy (the expertise of the Ashby laboratory) with established approaches to manipulate Tregs and inhibitory receptors.