Targeting LAG3+ T cells for Cancer Immunotherapy

Whilst an increasing number of malignancies can be controlled or even eradicated by immunotherapy, the majority (i.e. 85%) of colorectal cancer (CRC) remains stubbornly unresponsive, in particular to the blockade of immunological checkpoints with monoclonal antibodies (i.e. anti-CTLA4, -PD1 and -PDL1). Future efforts need to be directed at other targets in CRC that are driving immunosuppression, and there is evidence that LAG3 is an immune regulator expressed on TILs that could be targeted.

We hypothesise that LAG3-specific depleting antibodies will improve anti-tumour immune responses in CRC.
Aims

1. To test a series of anti-LAG3 blocking and depleting mAbs against CD4+ and CD8+ TILs extracted from CRC employing in vitro standard "2D" cultures and 3D patient-derived CRC organoids.

2. To use a transgenic mouse expressing human LAG3 (which will then be crossed with HLA-DR1 mice); test anti-LAG3 Abs in the hLAG3/HLA-DR1 mice using models of CRC.

The student will acquire skills in human cellular immunology (including establishment of 3D cultures), in vivo mouse models and imaging. Training in cellular immunology will be carried out by Andrew Godkin, in vivo mouse models (Awen Gallimore), organoid culture (Ann Williams) and imaging (Christoph Wuelfing). Each individual laboratory has a proven track record in training students in these areas.