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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.
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 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 exerted by tumor cells in response to endogenous immune anti-tumor activity. PD-L1 is overexpressed 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.
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.