Human PD1 verus mouse PD1 - how different are they? 3290

Abstract Description Mechanistic understanding of the inhibitory immunoreceptor PD1 is largely based on mouse models, but human and mouse PD1 orthologs exhibit only 59.6% identity in amino acid sequences. 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. Funding Sources Supported by R37 CA239072 from the National Institute of Health, the Hartwell Foundation, Human Frontiers Science Program and JST PRESTO grant (JPMJPR22EB) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)