The programmed cell death process

PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. PD-1 inhibitors, a the programmed cell death process class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer. The PD-1 protein in humans is encoded by the PDCD1 gene.

In a screen for genes involved in apoptosis, Yasumasa Ishida, Tasuku Honjo and colleagues at Kyoto University in 1992 discovered and named PD-1. PD-1 is a type I membrane protein of 268 amino acids. CTLA-4 family of T cell regulators. PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family.

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Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting this pathway as a target for immunotherapy. In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis. PD-L1, the ligand for PD1, is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. Combination therapy using both anti-PD1 along with anti-CTLA4 therapeutics have emerged as important tumor treatments within the field of checkpoint inhibition.

A combination of PD1 and CTLA4 antibodies has been shown to be more effective than either antibody alone in the treatment of a variety of cancers. The effects of the two antibodies do not appear to be redundant. In clinical trials, combination therapy has been shown to be effective in reducing tumor size in patients that are unresponsive to single co-inhibitory blockade, despite increasing levels of toxicity due to anti-CTLA4 treatment. T cells that are actively infiltrating the tumor tissue.

The molecular factors and receptors necessary making a tumor receptive to anti-PD1 treatment remains unknown. PDL1 expression on the surface on cancer cells plays a significant role. PDL1 positive tumors were twice as likely to respond to combination treatment. Higher mutational burden in the tumor is correlated with a greater effect of the anti-PD-1 treatment. In clinical trials, patients who benefited from anti-PD1 treatment had cancers, such as melanoma, bladder cancer, and gastric cancer, that had a median higher average number of mutations than the patients who do did not respond to the therapy. However, the correlation between higher tumor burden and the clinical effectiveness of PD-1 immune blockade is still uncertain.

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