Cancer immunotherapy and the PD-1/PD-L1 checkpoint pathway
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Learn about the PD-1/PD-L1 checkpoint pathway, its function in cancer, and how it is being used in immunotherapy.
What is the PD-1/PD-L1 pathway?
The PD-1 (programmed cell death-1) receptor (also known as CD279) is expressed on the surface of activated T cells. Its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), 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, which can halt or limit the development of the T cell response. 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.
See how PD-L1 is used as an immunotherapy biomarker
The role of PD-1/PD-L1 in cancer
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.
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Using PD-1/PD-L1 against cancer in immunotherapy
Monoclonal antibody therapies against PD-1 and PD-L1 are being now routinely used including Nivolumab; an anti-PD-1 drug developed by Bristol-Myers Squibb, which is approved for previously treated metastatic melanoma and squamous non-small cell lung cancer. Another anti-PD1 drug, Pembrolizumab, developed by Merck is approved for previously treated metastatic melanoma.
Similar strategies are being explored targeting PD-L1 to treat other cancer types including non-squamous non-small cell lung cancer, renal cell carcinoma and bladder cancer. MEDI4736, a new anti-PD-L1 drug developed by Astrazeneca is shown to be effective in early clinical trials. Roche’s leading anti-PD-L1 candidate drug, Atezolizumab (MPDL3280A), has shown significant benefits in clinical trials.
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References
1. Chen D and Mellman I, Oncology Meets Immunology: The Cancer-Immunity Cycle, Immunity 39, 2013.
