Professor Wooldridge’s team has used an Elizabeth Blackwell Institute Translational Acceleration and Knowledge Transfer award (TRACK) to start making inroads into new ways to manipulate immune cells to make them ‘see’ cancers and attack the cells more efficiently.
Now for the science behind this…
Cytotoxic T cells, also known as a CD8+ T-cells, are types of white blood cell found in the body that kill cancerous, or infected cells. However, their ability to kill cancerous cells in particular is compromised by the immunosuppressant environment that tumours create, and the fact that the T-cells express quite low affinity receptors at their surface; in a nutshell, they’re not very good at recognizing and killing cancer cells.
To understand what could be done about this, consider that CD8+ T-cells have receptors on their surface (called TCRs) that can recognise molecules on their target cells called antigens, which in turn trigger an immune response. These antigens are carried to the cell surface by molecules called MHCI (Major Histocompatibility complex Class I) molecules.
As well as the TCR, CD8+ T-cells also express a molecule called CD8. Once the TCRs have recognised an antigen, it is CD8 that binds to the MHCI on the target cell, although they bind with weak affinity.
Professor Wooldridge’s team is developing novel CD8 molecules which are capable of binding much more strongly to the MHCI and so increasing the ability of the CD8+ T-cells to fight cancer.
Firstly, the new higher affinity CD8 molecules needed to be designed; molecular modelling based on the structure of CD8, by team member Dr Richard Sessions, produced five candidate mutations. These then needed to be evaluated to make sure they are actually of higher affinity to MHCI complexes, and these then needed to be inserted into viruses, which were used to get the molecules onto the surface of the T-cells.
Professor Wooldridge’s team have found that at least one of the five candidate mutations results in increased recognition of MHCI at the cell surface.
Professor Wooldridge said, “This is extremely promising - and as a result, Dr Sessions and I went on to secure an ERC funded International Training Network (ITN) Grant. This involves ten European partners, who are all experts in cancer immunotherapy and collaborations with industry (ImmetacyteLtd). This is allowing us to perform more replicates of our studies and in-depth functional characterisation of the CD8 mutants developed in Bristol as a result of the TRACK award.