Development of Cytomegalovirus-Based Vectors in Cancer Vaccination
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Medicine
Abstract
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.
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.
Organisations
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013794/1 | 01/10/2016 | 30/09/2025 | |||
1943686 | Studentship | MR/N013794/1 | 01/10/2017 | 30/09/2021 | Carissa Wong |
Description | Dr Jenner's House Museum Discovery Day. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I volunteered to run a British Society of Immunology activity stall at the museum to teach the public about microbes, vaccination and herd immunity. |
Year(s) Of Engagement Activity | 2019 |
Description | FUTURES 2019, Up Late, We The Curious. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I built an online game that taught the public about T-cells and how they defend against microbes in the body. In addition, I ran a stall on herd immunity. |
Year(s) Of Engagement Activity | 2019 |