30th December 2024

Immune checkpoints and ICIs

Immune checkpoints

T cells are involved in the recognition and destruction of non-self cells, including malignant cells. T cells express certain transmembrane proteins that, when bound, modulate T-cell response. These proteins include programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Very broadly, binding of these proteins inhibits T cells from destroying cells. These receptors are known as immune checkpoints and in normal immune function prevent the immune system from destroying healthy self cells. It may be helpful to imagine immune checkpoints as ‘brakes’ on the immune system.

Cancer cells may exploit immune checkpoints by ‘turning on the brakes’

Tumour cells are able to proliferate without limit in part by evading the normal T cell-mediated immune response to non-self cells. This may be by exploiting immune checkpoints or ‘putting the brakes on’. For example, malignant cells may display proteins such as programmed cell death ligand-1 (PD-L1) that binds PD-1 and activates the T cell immune checkpoint (or turns on ‘the brakes’ on the immune system), preventing tumour cell destruction.

ICIs ‘take the brakes off’ at immune checkpoints

ICIs are drugs that we can administer to harness the immune system to destroy malignant cells. They are monoclonal antibodies that interact with immune checkpoints. Their targets may be T-cell receptors (such as PD-1 and CTLA-4) or tumour cell proteins (such as PDL-1). They bind these proteins and inhibit their function in immune checkpoints, thus ‘releasing the brakes’ on these T cells. This promotes T cell-mediated destruction of non-self and malignant cells.

However, releasing these immune checkpoint ‘brakes’ also increases the risk of immune-mediated destruction of healthy tissues. This can result in immune-mediated toxicity in any tissue.

Examples of ICIs

There are many ICIs in clinical practice useful to recognise commonly used ICIs. Summarised below are some common ICIs and their targets.