Immune Checkpoint Mechanism of Action

What is an Immune Checkpoint?

The immune system needs to differentiate between normal and abnormal cells. When the immune system identifies cells properly, it is able to destroy abnormal cells while not harming normal cells. Immune cells utilize checkpoints to perform this task. Immune checkpoints are cell surface proteins on T-cells that are able to bind homologous receptor proteins on other cells, such as an antigen presenting cell (APC). Activation of the immune checkpoint pathways results in either immune suppression or stimulation. Immune checkpoint pathways play a vital role in regulating the immune system, ultimately balancing its function and maintaining homeostasis.

Anti-tumor Immunity and Cancer Progression

Tumor cells adapt by learning to exploit checkpoint mechanisms. Tumor cells confuse T-cells by presenting cell surface proteins that are recognized as normal by the T-cell, even though they are unwanted and should be eliminated by the immune system. Checkpoint pathway manipulation is one strategy tumor cells employ to outsmart the immune system, survive, and proliferate freely.

Cancer and Checkpoint Inhibitors

An example of tumor cells evading immune response can be understood through the PD-1 and PD-L1 interaction. PD-1 is a checkpoint protein on T-cells that recognizes the cellular surface protein, PD-L1, which acts to prevent the attack of other cells. One strategy tumor cells employ to avoid an immune attack is through expression of PD-L1. Upon binding of PD-1 to PD-L1, immune suppression signals are sent which indicates to the immune system not to attack the tumor cell.

Checkpoint inhibitors are a class of monoclonal antibodies designed to target and bind to checkpoint proteins and block checkpoint signals (immune activation or suppression). Checkpoint inhibitors can bind to proteins on T-cells, such as PD-1, or protein receptors on tumor cells, such as PD-L1. Whether the checkpoint inhibitor binds to PD-1 or PD-L1, the PD-1/PD-L1 interaction is prevented and the signal is blocked. The power of checkpoint inhibitors as an immunotherapeutic method is being diligently investigated. Checkpoint inhibitor drugs have been successful in treating some forms of cancer and show great promise as an effective treatment with fewer symptoms than traditional therapeutic methods.

Congratulations to James P. Allison and Tasuku Honjo for their pioneering work and discovery of immune checkpoint proteins and winning the Nobel Prize in Physiology or Medicine.