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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, raising the question of potential cross-species functional differences. Based on our biochemical evidence that human PD1 is more inhibitory than mouse PD1, we addressed the functional consequence of PD1 humanization in a mouse melanoma model with adoptively transferred T cells. Using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), we found that humanization of PD1 intracellular domain (ICD) in CD8 T cells decreases the numbers, effector functions, and differentiation of intratumoral T cells. Specifically, PD1 humanization reduced the number of effector-like exhausted T cell subset while increasing the precursor-exhausted T cell subset, the latter of which is known to respond to anti-PD(L)1 therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE280853 | GEO | 2024/11/05

REPOSITORIES: GEO

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PD1 completely suppresses the transcriptional response induced by the T cell receptor

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