Are mice reliable models for PD-1 studies?
Mouse PD-1 is significantly weaker than human PD-1, which could have implications for using mice as models in PD-1 studies.
Programmed cell death protein 1 (PD-1) has been a key target for cancer treatments since its discovery in the 1990s; but how accurate are the models we use? Researchers at the University of California San Diego (UCSD; CA, USA) and the Chinese Academy of Sciences (Beijing, China) have found that mouse PD-1 is significantly weaker than the human version, meaning that mice may not be reliable models for studies involving PD-1.
PD-1 is a cell-surface receptor that resides on T and B cells, keeping immune cells from attacking other cells within the body. This prevents autoimmune diseases but also prevents the immune system from killing cancer cells. Researchers have developed drugs that block PD-1, unleashing the immune system to fight cancer; however, these drugs are only effective in a small percentage of patients, highlighting the need to better understand PD-1.
Much of our understanding of PD-1’s functions, like many proteins, comes from studies in mice, based on the assumption that rodent and human biology operate similarly. However, human and mouse PD-1 share less than 60% of their amino acid identity. To investigate the differences between human and mouse PD-1, the researchers carried out a series of biochemical analyses and animal modeling and developed a new evolutionary map that traced PD-1 back millions of years.
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They identified a PD-1 motif that is present in most mammals, including humans, but is surprisingly absent in rodents. The evolutionary analyses suggest that this motif could have been lost after a mass extinction event over 66 million years ago. The absence of this motif makes mouse PD-1 significantly weaker than human PD-1.
“Although many proteins in mice and humans have similar sequences, receptors in the immune system often show greater differences,” explained first author Takeya Masubuchi (UCSD). “Our study shows that these sequence differences can lead to functional variations of immune checkpoint receptors across species.”
The researchers then investigated the impact of PD-1 humanization in mice. They replaced mouse PD-1 with human PD-1 and found that this reduced tumor-specific T-cell responses in mice.
Further research is needed to understand the impact of humanized PD-1 on the anti-tumor activity of T cells, but the study calls us to question whether mice are a suitable model for PD-1.
“This study shows that as science progresses, we need to have a rigorous understanding of the model systems that we use to develop medicines and drugs,” commented co-senior author Jack Bui (UCSD). “Finding that rodents might be outliers in terms of PD-1 activity forces us to rethink how to deploy medicines to people. If we’ve been testing medicines in rodents and they’re really outliers, we might need better model systems.”
