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

Area of Science:

• Immunology
• Molecular Biology
• Evolutionary Biology

Background:

• Understanding programmed cell death protein 1 (PD-1) inhibition is crucial for cancer immunotherapy.
• Existing knowledge primarily relies on mouse models, despite significant amino acid divergence between human and mouse PD-1 (59.6% identity).

Purpose of the Study:

• To investigate the functional differences between human and mouse PD-1.
• To elucidate the molecular mechanisms underlying these species-specific variations.
• To assess the impact of human PD-1 function in a preclinical cancer model.

Main Methods:

• Comparative analysis of human and mouse PD-1 interactions with PD-L1 and PD-L2.
• Assessment of Shp2 phosphatase recruitment to PD-1.
• Functional evaluation of humanized PD-1 in a mouse melanoma model with adoptively transferred T cells.
• Identification and evolutionary analysis of conserved PD-1 motifs.

Main Results:

• Human PD-1 exhibits stronger inhibitory function compared to mouse PD-1.
• Human PD-1 demonstrates enhanced binding to PD-L1/PD-L2 and more efficient Shp2 recruitment.
• Humanization of the PD-1 intracellular domain in mice impaired CD8+ T cell antitumor activity and amplified anti-PD-1 responses.
• A conserved motif, absent in rodents, was identified as critical for differential Shp2 recruitment, suggesting rodent-specific functional attenuation of PD-1.

Conclusions:

• Significant species-specific differences exist in PD-1 pathway function between humans and rodents.
• These differences impact the efficacy of anti-PD-1 therapies and the translatability of mouse models.
• The findings have critical implications for the evolution of immune checkpoints and the development of more effective immunotherapies.