How are immune checkpoint inhibitors classified? What are their mechanisms of action
ICPIs have been developed targeting cytotoxic T lymphocyte–associated-protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1). These proteins play an important role in the development of peripheral immune self-tolerance and prevention of autoimmunity. Antigen presenting cells (APCs) activate T cells through the binding of antigens (either foreign antigens from infections or mutated self-antigens from cancer cells) on major histocompatibility complexes with T-cell receptors but require additional stimulation. CTLA-4 and PD-L1 receptors on T cells are part of a complex system of checkpoints that promote peripheral immune self-tolerance. CTLA-4 is the primary receptor that prevents activation of naïve T cells in lymph nodes and competes with its homolog receptor on T cells, cluster of differentiation 28 (CD28), for binding of CD80/CD86 on APCs. Binding of CD28 promotes T-cell activation and proliferation, whereas binding of CTLA-4 leads to anergy and reduced T-cell survival. PD-1 regulates previously activated T cells in the periphery and interacts with receptors for PD-L1 or programmed cell death ligand 2 (PD-L2) on peripheral cells to further promote self-tolerance through reduced T-cell activation and survival. Cancer cells have found ways to take advantage of this peripheral tolerance system to evade the immune system. ICPIs block these normal protein interactions, thereby removing the “brakes” on the immune system and resulting in enhanced T cell–mediated death of cancer cells, as well as the adverse endocrinopathies
