PD-1 and PDL-1 Blockade

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PD-1 and PDL-1 Blockade
History
For the past two decades, many studies in regards to cancer immune escape have shown that one of the critical mechanism is an immune checkpoint that is facilitated by programmed cell death one (PD-1) and its first ligand (PD-L1) in the tumor environment. PD-1 discovery is attributed to Tasuku Honjo and his colleagues at Kyoto University, 1992 (Hamanishi, Junzo, et al.). PD-1 that is encoded by the PGCD1 gene was initially detected by looking at the genes involved in stimulating induced programmed cell death in various B-cell lines and murine T-cell lines. Consequently, the human homolog PDCD1 was identified and isolated with the help of murine PD-1 probe to show human T-lymphocyte DNA components in 1994. The PD-1 structure has three domains namely; N-terminal, Transmembrane, and the C-terminal.
What PD-1 and PDL-1 Blockade does
Programmed cell death-1 (PD-1) that is generally expressed on T-cells is known to negatively regulate their antitumor impact. PD-L1 often engages with PD-1 to stop the production and proliferation by T-lymphocyte cells. Under normal conditions, studies show that PD-L1 is expressed in the lungs, tonsil, monocytes, and syncytiotrophoblast, with their main function being immune tolerance (Hamanishi, Junzo, et al.). In addition, PD-L1 is also expressed in various human cancers such as melanoma, ovarian cancer, lung cancer, urothelial cancer, breast cancer, and the immune cells that infiltrate the tumor environment.

Several studies, therefore, show that stopping the interaction between PD-1 and PD-L1 improves T-lymphocytes functions in fighting off tumor activity (Zheng, Peilin, and Zhiguang Zhou). In essence, the PD-1 and PD-L1 blockade is effective in combating cancer cells. With the tumor microenvironment being extremely immune suppressive, blocking the PD-1 and PD-L1 pathway aids in countering tumor proliferation. It is an important cancer therapeutic procedure that is still undergoing various clinical trials.
Cells respond to it
PD-1 and PD-L1 blockade is different from other cancer therapeutic procedures in that it can be well tolerated by body cells. It is not cell poison. Adverse reactions to this immunotherapy include nausea and autoimmune-mediated cellular events that might lead to conditions such as pneumonitis and colitis (Zheng, Peilin, and Zhiguang Zhou). Such adverse reactions are however minimal and have only been reported in less than 10% of patients.
How cells respond to cancer situation
Notably, studies have shown that PD-1 and PD-L1 blockade is most effective in patients that have high levels of PD-1 and PD-L1 expression. In different clinical trials, the principle of the blockade is to develop human IgG to bind onto either the ligand or PD-1, hence, inhibiting PD-1 and PD-L1 ligation and the consequent signaling events (Zheng, Peilin, and Zhiguang Zhou). This increases the killing of tumor cells facilitated by either increased production of cytokines (IFN-ỿ). The PD-1/PD-L1 blockade often works in the tumor microenvironment. The blockade has been quite effective in mitigating different types of cancer such as melanoma, bladder, lung, liver, kidney, and esophageal cancer. In particular, it has been quite essential in Hodgkin therapy, but rather inefficient in both colon and brain cancer.
In addition, the PD-L1 expression on the cancer cells increases the chances of a positive response to the PD-1/PD-L1 blockade in that there is a high chance of positive response of the blockade in patients with tumors expressing positive PD-L1 than those that express negative PD-L1. In short, as opposed to other therapeutic procedures, cancer immunotherapy does not target cancer cells nor turn on immune responses, instead, it functions by blocking inhibitory pathways in order to generate anti-tumor immune responses.
Work cited
Hamanishi, Junzo, et al. “PD-1/PD-L1 blockade in cancer treatment: perspectives and issues.” International journal of clinical oncology 21.3 (2016): 462-473.
Zheng, Peilin, and Zhiguang Zhou. “Human cancer immunotherapy with PD-1/PD-L1 blockade.” Biomarkers in cancer 7 (2015): BIC-S29325.