2024/10/23 by Xuetong Wang, Tongfeng Liu, Yifei Li +12 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · #Cancer Immunotherapy and Biomarkers #Immune Cell Function and Interaction #RNA Research and Splicing
paper · pdf · doi:10.1038/s41467-024-53561-2
openalex publication_date 2024/10/23 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
The immune checkpoint receptor, programmed cell death 1 (PD-1, encoded by PDCD1), mediates the immune escape of cancer, but whether PD-1 splicing isoforms contribute to this process is still unclear. Here, we identify an alternative splicing isoform of human PD-1, which carries a 28-base pairs extension retained from 5′ region of intron 2 (PD-128), is expressed in peripheral T cells and tumor infiltrating lymphocytes. PD-128 expression is induced on T cells upon activation and is regulated by an RNA binding protein, TAF15. Functionally, PD-128 inhibits T cell proliferation, cytokine production, and tumor cell killing in vitro. In vivo, T cell-specific exogenous expression of PD-128 promotes tumor growth in both a syngeneic mouse tumor model and humanized NOG mice inoculated with human lung cancer cells. Our study thus demonstrates that PD-128 functions as an immune checkpoint, and may contribute to resistance to immune checkpoint blockade therapy. Whether PD-1 splicing isoforms impact T cell anti-tumor capacity has not been fully illustrated. Here the authors identify a human PD-1 isoform, PD-128, which functions to suppress anti-cancer immunity in vitro and in both syngeneic and humanized mouse tumor models.