HuPD-H1 knock-in/knock-out mice have the extracellular domains of both mouse Pdcd1 (PD-1) and Cd274 (PD-L1) replaced with the corresponding human PDCD1 and CD274 sequences. The remaining mouse exons of each gene were kept intact to ensure normal downstream signals from each molecule within the cytoplasm. Cd274 encodes PD-L1, one of two ligands for PD-1 that is upregulated on antigen presenting cells (APCs), activated T cells, myeloid cells, dendritic cells (DCs). It is also expressed on hematopoietic and parenchymal cells. PD-1 is an inhibitory receptor expressed on activated lymphocytes where it regulates tolerance and autoimmunity by negative regulation of T cell responses. Immune checkpoint blockade (IBC) therapy has been used as a treatment for multiple cancer types. It involves the use of antibodies that target T cell co-receptors, such as therapies targeting PD-1/PD-L1 signaling, yet many FDA-approved mAbs targeting PD-1 and PD-L1 do not cross-react between human and mouse proteins. When an in vivo T cell priming assay, in which anti-PD-1/L1 therapies are given at the time of T cell priming against surrogate tumor Ag (OVA), followed by subsequent B16-OVA tumor challenge, both control and Ab-treated HuPD-H1 mice form an equally robust OVA-specific T cell response at the time of priming. Despite this, anti-PD-1/L1-treated mice exhibit significantly better tumor rejection versus controls. These mice are a critical tool for optimizing and better utilizing FDA-approved antiPD-1/L1 therapeutics. Mice homozygous for both mutations are viable and fertile.

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HuPD-H1 knock-in/knock-out mice have the extracellular domains of both mouse Pdcd1 (PD-1) and Cd274 (PD-L1) replaced with the corresponding human PDCD1 and CD274 sequences. The remaining mouse exons of each gene were kept intact to ensure normal downstream signals from each molecule within the cytoplasm. These mice are a useful tool that will decrease the distance between the preclinical and clinical space and accelerate translational studies to further improve PD-1/L1 therapy.

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