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Cited by 36Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmune Cell Function and Interaction

Functional differences between rodent and human PD-1 linked to evolutionary divergence

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Masubuchi, Takeya, Chen, Lin, Marcel, Nimi, Wen, George A., Caron, Christine, Zhang, Jibin, Zhao, Yunlong, Morris, Gerald P. +7 more·2025·Science Immunology
DOI 10.1126/sciimmunol.ads6295PMC PMC11774210
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Abstract

Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2. In a mouse melanoma model with adoptively transferred T cells, humanization of a PD-1 intracellular domain disrupted the antitumor activity of CD8 + T cells and increased the magnitude of anti–PD-1 response. We identified a motif highly conserved across vertebrate PD-1 orthologs, absent in rodents, as a key determinant for differential Shp2 recruitment. Evolutionary analysis suggested that PD-1 underwent a rodent lineage–specific functional attenuation during evolution. Together, our study uncovers species-specific features of the PD-1 pathway, with implications for PD-1 evolution and differential anti–PD-(L)1 responses in mouse models and human patients.

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  • Mouse immune systems differ from humans in key aspects, including cytokine signaling, immune cell ratios, and pattern recognition receptor expression.

    “Mouse immune systems differ from humans in key aspects, including cytokine signaling, immune cell ratios, and pattern recognition receptor expression [158]”

    From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [158]

    The Introduction (page not available in our copy) says mice and humans differ in the relative abundance of immune cell types, supporting the claim about immune cell ratios. It also mentions gene-expression and gene-function differences, but does not identify cytokine signaling or pattern-recognition receptor expression as examples; the Discussion addresses PD-1 signaling instead. (LLM, conf=0.88)

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Authors
Masubuchi, T., Chen, L., Marcel, N., Wen, G. A., Caron, C., Zhang, J., Zhao, Y., Morris, G. P., Chen, X., Hedrick, S. M., Lu, L.-F., Wu, C., Zou, Z., Bui, J. D., & Hui, E.
Affiliations
  • University of California San Diego (US)
  • Chinese Academy of Sciences (CN)
  • Department of Molecular Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
  • National Institutes of Health (US)
Corresponding author
  • Chen, Lin
  • Marcel, Nimi
  • Wen, George A.
  • Zou, Zhengting
  • Bui, Jack D.
  • Hui, Enfu
ORCID
Venue
Science Immunology
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-01-03
Volume
10
Issue
103
Pages
eads6295-eads6295
ISSN
2470-9468 (ISSN-L)
DOI
10.1126/sciimmunol.ads6295
PMC
PMC11774210
OpenAlex
W4406027968
Cited by
36
References
7
Citations by year
2026: 16 · 2025: 20
FWCI
14.82
Type
journal article
Language
en
Open access
Locations
  • Science Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (1s10od026929-01)
  • University of California, San Diego (#S10 OD026929)
  • National Institute on Aging (R01AG074273, R01AG078185)
  • National Cancer Institute (R37CA239072)
  • National Institute of Allergy and Infectious Diseases (R21AI178396, R01AI108651)
  • Precursory Research for Embryonic Science and Technology
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords
PD-1, PD-L1, PD-L2, SHP2, species differences, humanization, melanoma, CD8+ T cells, anti-PD-1 therapy, evolutionary divergence
MeSH terms
Animals, Humans, Mice, Inbred C57BL, Species Specificity, CD8-Positive T-Lymphocytes, Evolution, Molecular, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Programmed Cell Death 1 Ligand 2 Protein

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