Much of our understanding of the protein PD-1, a crucial target for cancer therapy, has been derived from mouse studies. Recent research reveals that the PD-1 found in mice is considerably less effective than its human counterpart, shedding light on the advancement of cancer treatments.
Since it was identified in the 1990s, “programmed cell death protein 1” (PD-1) has been a prominent focus in cancer therapy. This “checkpoint” receptor, commonly located on immune cells, acts like an off switch, preventing these immune cells from attacking healthy tissues.
Following its discovery, which transformed oncology and was recognized with a Nobel Prize in 2018, scientists began developing new medications aimed at inhibiting PD-1 to reactivate the immune system’s ability to combat cancer. However, the effectiveness of PD-1-targeting treatments is limited to a small portion of cancer patients, pointing to the necessity for further investigation into the mechanisms of PD-1. Much of what we know about PD-1’s role comes from studies conducted on mice, based on the belief that rodent and human biology are comparable.
Researchers from UC San Diego’s School of Biological Sciences and School of Medicine have now revealed that this belief may be incorrect. Through an extensive examination of PD-1 featuring innovative biochemical studies, animal modeling, and a new evolutionary history extending back millions of years, scientists at UC San Diego and their colleagues from the Chinese Academy of Sciences discovered that PD-1 in mice is notably less potent than in humans.
Led by assistant project scientist Takeya Masubuchi, the study unveiled several unknown characteristics of PD-1, including a unique “motif”—a specific arrangement of amino acids—that varies greatly between rodents and humans.
“Our findings highlight unexpected species-specific traits of PD-1 that could influence the creation of improved preclinical models for PD-1,” commented Associate Professor Enfu Hui from the Department of Cell and Developmental Biology and a senior author of the study. “We identified a motif associated with PD-1 that exists in most mammals, including humans, but is unexpectedly absent in rodents, which results in a uniquely lesser form of PD-1 in those animals.”
The study’s findings are published on January 3, 2025, in the journal Science Immunology.
“While many proteins in mice and humans share similar sequences, immune system receptors tend to exhibit greater disparities,” Masubuchi noted. “This research demonstrates how these sequence differences can result in functional variations in immune checkpoint receptors among different species.”
Expanding their research, scientists evaluated the effects of replacing mouse PD-1 with human PD-1 in mice—an endeavor carried out in Professor Jack Bui’s lab in the Department of Pathology. They discovered that this humanization of PD-1 hindered the ability of immune cells (T cells) to attack tumors.
“This study underscores the importance of thoroughly understanding the model systems we rely on to develop drugs as scientific knowledge advances,” stated Bui. “The realization that rodents may be anomalies regarding PD-1 function necessitates a reevaluation of how we implement treatments for humans. If our drug tests are based on rodent models that are significantly different, we might require improved test systems.”
In collaboration with co-senior author Professor Zhengting Zou and his colleagues from the Chinese Academy of Sciences, the researchers explored how PD-1 differs between humans and rodents over time. They found evidence suggesting a significant decline in the activity of ancestral rodent PD-1 approximately 66 million years ago, following the Cretaceous-Paleogene (K-Pg) mass extinction, which led to the extinction of non-avian dinosaurs. Their findings indicate that rodent PD-1 is uniquely weak compared to all vertebrates, potentially due to specific ecological adaptations that helped these animals survive rodent-centric pathogens.
“The ancestors of rodents managed to survive the mass extinction, but their immune receptor functions may have been modified in response to new environmental pressures,” Hui explained.
Future research will explore how PD-1 influences the anti-tumor responses of T cells in a human-like context across different types of tumors.
