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Published on: September 28, 2018
Evolutionary fingerprint in rodent PD1 confers weakened activity and enhanced tumor immunity compared to human PD1
Abstract:
Mechanistic understanding of the immune checkpoint receptor PD1 is largely based on mouse models, but human and mouse PD1 orthologs exhibit only 59.6% identity in amino acid sequences. Here we show that human PD1 is more inhibitory than mouse PD1 due to stronger interactions with the ligands PDL1 and PDL2 and with the effector phosphatase Shp2. A novel motif highly conserved among PD1 orthologs in vertebrates except in rodents is primarily responsible for the differential Shp2 recruitment. Evolutionary analysis suggested that rodent PD1 orthologs uniquely underwent functional relaxation, particularly during the K-Pg boundary. Humanization of the PD1 intracellular domain disrupted the anti-tumor activity of mouse T cells while increasing the magnitude of anti-PD1 response. Together, our study uncovers species-specific features of the PD1 pathway, with implications to PD1 evolution and differential anti-PD(L)1 responses in mouse models and human patients.
Insights
Human PD1 is more inhibitory than mouse PD1 due to stronger interactions. Rodent PD1 underwent functional relaxation, impacting anti-tumor immunity and anti-PD1 responses in research models.
Area of Science:
- Immunology
- Evolutionary Biology
- Molecular Biology
Background:
- Immune checkpoint receptor programmed cell death protein 1 (PD1) function is primarily studied in mouse models.
- Human and mouse PD1 proteins share only 59.6% amino acid identity, suggesting potential species-specific differences.
Purpose of the Study:
- To investigate the mechanistic differences between human and mouse PD1 signaling.
- To explore the evolutionary basis for these species-specific variations.
- To assess the implications for anti-PD1/PDL1 cancer immunotherapy.
Main Methods:
- Comparative analysis of human and mouse PD1 protein sequences and interactions.
- Biochemical assays to measure binding affinities with PDL1, PDL2, and Shp2 phosphatase.
- Evolutionary analysis of PD1 orthologs across vertebrate species.
- Functional studies using humanized mouse models to assess T cell activity and therapeutic response.
Main Results:
- Human PD1 exhibits stronger inhibitory interactions with its ligands (PDL1, PDL2) and the phosphatase Shp2 compared to mouse PD1.
- A novel conserved motif in human PD1, absent in rodents, is critical for enhanced Shp2 recruitment.
- Evolutionary analysis indicates functional relaxation of rodent PD1, particularly around the K-Pg boundary.
- Humanization of mouse PD1 disrupted anti-tumor T cell activity and altered the efficacy of anti-PD1 therapy.
Conclusions:
- Significant species-specific differences exist in PD1 pathway function, with human PD1 being more potent.
- Rodent PD1 has undergone functional relaxation, potentially limiting its translatability to human cancer immunotherapy.
- Understanding these evolutionary and mechanistic variations is crucial for interpreting mouse model data and improving anti-PD1/PDL1 therapies.
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