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.

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using anti-LAG3 antibodies, can actually increase the suppressive capacity of human CD4+LAG3+ T cells1 (Figure 1; unpublished data), through enhanced IL-10 production.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.