Since the 1990s, PD-1 has been a key target in cancer treatments due to its role as a checkpoint receptor on immune system cells that regulates immune responses. While drugs targeting PD-1 have been developed to unleash the body’s immune system against cancer, these treatments are only effective in a small percentage of patients, indicating a need for a deeper understanding of PD-1’s functions. Most knowledge about PD-1 comes from studies in mice, assuming that rodent and human biology are similar.
Researchers at UC San Diego’s School of Biological Sciences and School of Medicine have discovered significant differences in PD-1 between mice and humans. Through comprehensive analyses including biochemical studies, animal modeling, and an evolutionary roadmap tracing PD-1 back millions of years, the scientists found that mouse PD-1 is weaker than its human counterpart. This study, led by assistant project scientist Takeya Masubuchi, uncovered unique characteristics of PD-1 in rodents compared to humans, such as a specific amino acid sequence motif that is absent in mice.
The study, published in Science Immunology in 2025, sheds light on the importance of understanding species-specific features of immune checkpoint receptors like PD-1 when developing pre-clinical models and treatments. Testing the impact of humanizing PD-1 in mice, researchers found that replacing mouse PD-1 with the human version disrupted the ability of immune cells (T cells) to fight tumors. Co-senior author Professor Jack Bui emphasized the need for a thorough understanding of model systems used in drug development, especially if rodents are outliers in terms of PD-1 activity.
Collaborating with Chinese Academy of Sciences colleagues, the researchers traced the differences between human and rodent PD-1 back to 66 million years ago, after the mass extinction event that wiped out non-avian dinosaurs. An analysis revealed that rodent PD-1 underwent a significant decrease in activity following this event, making it uniquely weak among vertebrates. This weakening may have been a result of ecological adaptations to new environmental challenges and specific pathogens that rodents faced.
Future studies will focus on assessing the impact of PD-1 on T cell anti-tumor activity in a humanized context across various tumor types. The findings from this research highlight the importance of considering species-specific differences when developing cancer treatments that target immune checkpoint receptors like PD-1. Understanding these variations can lead to more effective pre-clinical models and personalized therapies for patients based on their specific biological makeup.
