Revealing Insights: Unexpected Variations Between Humans and Mice in Key Cancer Immunotherapy Targets

In expanding their research, the scientists examined the effect of PD-1 humanization in mice — substituting mouse PD-1 with the human variant — via co-senior author Professor Jack Bui’s lab in the Department of Pathology. They observed that PD-1 humanization hindered the capacity of immune cells (T cells) to make headway against tumors.

“This study indicates that as scientific knowledge evolves, we must thoroughly grasp the model systems utilized in developing pharmaceuticals and treatments,” stated Bui. “The revelation that rodents might be exceptional in terms of PD-1 function prompts us to reconsider how we administer treatments to humans. If we have been testing therapies in rodents and they are indeed anomalies, it suggests we require more effective model systems.”

To investigate the historical differences in PD-1 between humans and rodents, the researchers joined efforts with co-senior author Professor Zhengting Zou and his colleagues from the Chinese Academy of Sciences. They uncovered signs of a significant decline in ancestral rodent PD-1 function approximately 66 million years ago following the Cretaceous–Paleogene (K–Pg) mass extinction event, which eradicated the (non-avian) dinosaurs. Their analysis revealed that rodent PD-1 is remarkably weak compared to other vertebrates. This diminishing effect may be linked to unique ecological adaptations developed to evade the impacts of rodent-specific pathogens.

“The ancestors of rodents endured the extinction event, but their immune receptor functions or landscapes may have been modified due to adaptations to new environmental pressures,” remarked Hui.

Future research will evaluate the influence of PD-1 on the anti-tumor capabilities of T cells in a humanized setting across diverse tumor types.

The complete author list includes: Takeya Masubuchi, Lin Chen, Nimi Marcel, George Wen, Christine Caron, Jibin Zhang, Yunlong Zhao, Gerald Morris, Xu Chen, Stephen Hedrick, Li-Fan Lu, Chuan Wu, Zhengting Zou, Jack Bui, and Enfu Hui.

The study received funding from the National Institutes of Health (grants R37 CA239072, R01AG074273, and R01AG078185), the Human Frontier Science Program, the Japan Science and Technology Agency (JST) PRESTO grant (JPMJPR22EB), the American Cancer Society (grant AWD103481), the Hartwell Foundation, a Searle Scholar Award from the Kinship Foundation, and a Pew Biomedical Scholar Award from the Pew Charitable Trusts.

Disclosures of competing interests: Hui provides consultancy for Tentarix Biotherapeutics. Bui consults for Valora and DrKumo and acts as chief scientific officer for Paramita Therapeutics and Pathfinder.