[8][9] PD-1 inhibitors, a new class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer.

In a screen for genes involved in apoptosis, Yasumasa Ishida, Tasuku Honjo and colleagues at Kyoto University in 1992 discovered and named PD-1.

[11][12] In 1999, the same group demonstrated that mice where PD-1 was knocked down were prone to autoimmune disease and hence concluded that PD-1 was a negative regulator of immune responses.

In addition, PD-1 ligation up-regulates E3 ubiquitin ligases CBL-b and c-CBL that trigger T cell receptor down-modulation.

Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV viral vector model of chronic infection, Rafi Ahmed's group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.

[19][20] 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.

[26] In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis.

Mice deficient for this gene bred on a BALB/c background developed dilated cardiomyopathy and died from congestive heart failure.

These studies suggest that this gene product may also be important in T cell function and contribute to the prevention of autoimmune diseases.

[7][31] Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity.

[7][35][36] 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.

[38] The 2018 Nobel Prize for Medicine was awarded to James P Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation".

Nivolumab (Opdivo, Bristol-Myers Squibb) was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic melanoma.

On October 2, 2015, Pembrolizumab was approved by FDA for advanced (metastatic) non-small cell lung cancer (NSCLC) patients whose disease has progressed after other treatments.

[41][42][43] Drugs in early stage development targeting PD-1 receptors (checkpoint inhibitors) include pidilizumab (CT-011, Cure Tech) and BMS-936559 (Bristol Myers Squibb).

[46] Heightened presence of the PD-1 receptors corresponds to exhaustion of the HIV specific CD8+ cytotoxic and CD4+ helper T cell populations that are vital in combating the virus.