Targeting LAG3+ T cells for Cancer Immunotherapy
Application deadline: 23 November 2018
Start date: October 2019
Research theme: Infection, immunity and repair
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.
The membrane-expressed lymphocyte activation gene-3 (LAG3, CD223) is markedly up-regulated in CRC. It is expressed on a population of highly immunosuppressive IL-10-producing tumour-infiltrating CD4+ T cells (TILs). In chronic liver inflammation, LAG3+CD8+ T cells produce IL-102, thus it is likely that LAG3+ CD8+ T cells, enriched in CRC, also produce this highly immunosuppressive cytokine.
Currently, there are four blocking LAG3 antibodies in clinical development, yet many questions remain regarding the biology and function of LAG3. In particular, it has been shown that blocking LAG3 binding to its natural ligand (HLA class II antigens) using anti-LAG3 antibodies, can actually increase the suppressive capacity of human CD4+LAG3+ T cells1, through enhanced IL-10 production. Hence, removing these LAG3+ regulatory T cells is a more attractive approach if the aim is to unleash an anti-cancer immune response. The effects of depleting LAG3+ CD8+ T cell will also be measured below, for we believe in the context of tumours, these cells are also more likely to be suppressive in nature.
Project aims and methods
We hypothesise that LAG3-specific depleting antibodies will improve anti-tumour immune responses in CRC.
- 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.
- 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.
If the results support the hypothesis that a depleting antibody targeting LAG3 has potential clinical utility in treating CRC patients, we are poised to test a GMP grade depleting anti-LAG3 antibodies produced by a Biotech partner, in a Phase I clinical study.
You 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.
You will acquire skills in human cellular immunology (including establishment of 3D cultures), in vivo mouse models and imaging.