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Read about the PD-1/PD-L1 checkpoint pathway, its function in cancer, and how it is being used in immunotherapy.
Immune checkpoint inhibitors
The PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells. Its ligands, PD-L1 and PD-L2, are commonly expressed on the surface of dendritic cells or macrophages. PD-1 and PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors that can halt or limit the development of the T cell response. The PD-1/PD-L1 interaction ensures that the immune system is activated only at the appropriate time in order to minimize the possibility of chronic autoimmune inflammation.
Under normal conditions, the immune system performs a series of steps which lead to an anticancer immune response and cancer cell death, known as the cancer immunity cycle1:
1. Tumor cells produce mutated antigens that are captured by dendritic cells
2. The dendritic cells prime T cell with tumor antigen and stimulate the activation of cytotoxic T cells
3. Activated T cells then travel to the tumor and infiltrate the tumor environment
4. The activated T cells recognize and bind to the cancer cells
5. The bound effector T cells release cytotoxins, which induce apoptosis in their target cancer cells
The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is exerted by tumor cells in response to endogenous immune anti-tumor activity. PD-L1 is commonly over expressed on tumor cells or on non-transformed cells in the tumor microenvironment2. PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
Using PD-1/PD-L1 and immunotherapy
Monoclonal antibody therapies against PD-1 and PD-L1 are being routinely used including:
There are several other immunotherapy options being used or in development.
5. Grupp, S., Kalos, M., Barrett, D., Aplenc, R., Porter, D., Rheingold, S., Teachey, D., Chew, A., Hauck, B., Wright, J., Milone, M., Levine, B. and June, C. (2013). Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia. New England Journal of Medicine, 368(16), pp.1509-1518.