Since its discovery in the 1990s, “programmed cell death protein 1,” or PD-1, has been considered a prime target in cancer treatments. The PD-1 molecule, a “checkpoint” receptor that often resides on the surface of immune system cells, functions as a kind of off switch that prevents immune cells from attacking other cells.
After his discovery, which revolutionized oncology and earned him the Nobel Prize in 2018, researchers developed new drugs to block PD-1 and unleash the body’s immune system to fight cancer. However, treatments that harness PD-1 are only effective in a small fraction of cancer patients, highlighting the need for a deeper understanding of how PD-1 works. Much of our current knowledge about PD-1 functions comes from studies in mice, based on the assumption that rodent and human biology function similarly.
Researchers at UC San Diego School of Biological Sciences and Medicine have now discovered that this assumption may be wrong. In a comprehensive evaluation of PD-1 that included new biochemical analyses, animal models, and a new evolutionary roadmap that traces PD-1 back millions of years, UC San Diego scientists and their colleagues at the Chinese Academy of Sciences found that PD-1 in mice is significantly weaker than the human version.
The study, led by assistant project scientist Takeya Masubuchi, revealed several previously unknown features of PD-1, including a “motif” (a specific amino acid sequence) that is very different in rodents and humans.
“Our work uncovers unexpected species-specific features of PD-1 with implications for the development of better preclinical models for PD-1,” said Associate Professor Enfu Hui of the School of Biological Sciences, Department of Cell and Developmental Biology, and senior researcher. author of the article. “We found a motif in PD-1 that is present in most mammals, including humans, but is surprisingly missing in rodents, making rodent PD-1 exceptionally weaker.”
The results of the study are published on January 3, 2025 in the journal. Scientific immunology.
“Although many proteins in mice and humans have similar sequences, receptors in the immune system often show greater differences,” Masubuchi said. “Our study shows that these sequence differences can lead to functional variations of immune checkpoint receptors between species.”
In addition to their analysis, the researchers tested the impact of humanizing PD-1 in mice, replacing mouse PD-1 with the human version, through the laboratory of co-senior author Professor Jack Bui in the Department of Pathology. . They found that humanizing PD-1 altered the ability of immune cells (T cells) to fight tumors.
“This study shows that as science advances we need to have a rigorous understanding of the model systems we use to develop drugs,” Bui said. “Finding out that rodents might be outliers in terms of PD-1 activity forces us to rethink how to give drugs to people. If we’ve been testing drugs in rodents and they really are outliers, we may need better model systems.”
To track human-rodent PD-1 differences over time, the researchers collaborated with co-senior author Professor Zhengting Zou and colleagues at the Chinese Academy of Sciences. They discovered evidence of a major drop in ancestral rodent PD-1 activity about 66 million years ago after the Cretaceous-Paleogene (K-Pg) mass extinction event, which wiped out the (non-avian) dinosaurs. The analysis showed that rodent PD-1 is exceptionally weak among all vertebrates. The weakening may be attributed to special ecological adaptations to escape the effects of specific rodent pathogens.
“Rodent ancestors survived the extinction event, but their immune receptor activities or landscape could have been altered as a consequence of adaptation to new environmental challenges,” Hui said.
Future studies will evaluate the impact of PD-1 on T cell antitumor activity in a humanized context in various tumor types.