Unveiling the Disparities: How Human and Mouse PD-1 Diverge in Cancer Research

Since its identification in the 1990s, “programmed cell death protein 1,” or PD-1, has been perceived as a primary target in cancer therapies. A “checkpoint” receptor that typically exists on the exterior of immune system cells, the PD-1 molecule acts as a sort of off switch that prevents immune cells from assaulting other cells.

Following its discovery, which transformed oncology and garnered a 2018 Nobel Prize, scientists formulated new medications to inhibit PD-1 and activate the body’s immune system against cancer. However, treatments utilizing PD-1 are only successful in a limited percentage of cancer patients, underscoring the necessity for a more profound comprehension of PD-1’s operational mechanisms. A substantial portion of our present knowledge regarding PD-1’s roles derives from studies conducted on mice, based on the belief that rodent and human biology function similarly.

Researchers at UC San Diego’s School of Biological Sciences and School of Medicine have now uncovered that this belief may be misguided. In a thorough evaluation of PD-1 that included innovative biochemical assessments, animal models, and a new evolutionary trajectory tracing PD-1 back millions of years, the UC San Diego scientists along with their colleagues from the Chinese Academy of Sciences determined that PD-1 in mice is considerably less robust than its human counterpart.

The investigation, spearheaded by assistant project scientist Takeya Masubuchi, unveiled several previously unrecognized characteristics of PD-1, including a “motif” -; a distinct sequence of amino acids -; that is remarkably different in rodents and humans.

Our research reveals unexpected species-specific traits of PD-1 which have implications for creating improved pre-clinical models for PD-1. We identified a motif in PD-1 present in most mammals, including humans, but surprisingly absent in rodents, resulting in rodent PD-1 being distinctly weaker.”

Enfu Hui, Associate Professor, School of Biological Sciences, Department of Cell and Developmental Biology, and senior author of the publication

The findings of the research are published on January 3, 2025, in the journal Science Immunology.

“Although many proteins in both mice and humans exhibit comparable sequences, receptors within the immune system frequently demonstrate greater discrepancies,” stated Masubuchi. “Our research illustrates that these sequence variations can result in functional differences of immune checkpoint receptors across species.”

Expanding their examination, the researchers evaluated the effects of PD-1 humanization in mice -; substituting mouse PD-1 with the human variant -; through co-senior author Professor Jack Bui’s lab in the Department of Pathology. They discovered that PD-1 humanization impaired the capacity of immune cells (T cells) to counteract tumors.

“This research emphasizes that as scientific knowledge advances, we must have a stringent understanding of the model systems we utilize to create medications and drugs,” remarked Bui. “Realizing that rodents might represent outliers regarding PD-1 activity prompts us to reconsider how we administer medications to humans. If we have been testing medications in rodents and they are indeed outliers, we may require better model systems.”

To unveil the evolutionary differences of PD-1 between humans and rodents, the researchers collaborated with co-senior author Professor Zhengting Zou and his colleagues at the Chinese Academy of Sciences. They uncovered evidence of a significant decline in ancestral rodent PD-1 activity approximately 66 million years ago, following the Cretaceous–Paleogene (K–Pg) mass extinction event, which led to the extinction of non-avian dinosaurs. The analysis revealed that rodent PD-1 is uniquely weak compared to all vertebrates. This weakening may be linked to specific ecological adaptations to evade the effects of rodent-specific pathogens.

“The ancestors of rodents survived the extinction event, yet their immune receptor functions or landscape might have altered as an adaptation to new environmental difficulties,” stated Hui.

Future research endeavors will investigate the impact of PD-1 on the anti-tumor effectiveness of T cells in a humanized context across various types of tumors.