immunocheckpoints

Immunocheckpoints are regulatory pathways that control the intensity and duration of immune responses. They are crucial for maintaining self-tolerance and preventing autoimmune diseases, as well as for limiting tissue damage during an immune response to infection or cancer. These checkpoints involve interactions between specific molecules on immune cells, primarily T cells, and their counterparts on other cells, including antigen-presenting cells and target cells.

When an immune cell, such as a T cell, encounters an antigen, it becomes activated. However, immunocheckpoints act as a brake, preventing the immune response from becoming overactive. Key examples of immunocheckpoint molecules include PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). PD-1 is expressed on activated T cells, B cells, and myeloid cells, and its ligands, PD-L1 and PD-L2, are found on various cells, including tumor cells. Engagement of PD-1 with its ligands inhibits T cell activation and proliferation, leading to T cell exhaustion. CTLA-4 is primarily expressed on T cells and competes with CD28, a co-stimulatory molecule, for binding to B7 ligands on antigen-presenting cells. This interaction dampens T cell activation, particularly in the early stages of an immune response.

The discovery and understanding of immunocheckpoints have revolutionized cancer immunotherapy. By developing antibodies that block these checkpoints (known as checkpoint inhibitors), it is possible to unleash the immune system to attack cancer cells. These therapies have shown remarkable efficacy in treating various cancers, including melanoma, lung cancer, and kidney cancer, by reactivating T cells that were previously suppressed by the tumor microenvironment. However, blocking these natural brakes can also lead to immune-related adverse events, where the immune system attacks healthy tissues, resulting in autoimmune-like side effects.