A splicing isoform of PD-1 promotes tumor progression as a potential immune checkpoint

Xuetong Wang, Tongfeng Liu, Yifei Li, Ao Ding, Chang Zhang, Yinmin Gu, Xujie Zhao, Shuwen Cheng, Tianyou Cheng, Songzhe Wu, Liqiang Duan, Jihang Zhang, Rong Yin, Man Shang and Shan Gao ()
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Xuetong Wang: University of Science and Technology of China
Tongfeng Liu: Southeast University
Yifei Li: Southeast University
Ao Ding: Southeast University
Chang Zhang: Southeast University
Yinmin Gu: Southeast University
Xujie Zhao: Southeast University
Shuwen Cheng: Southeast University
Tianyou Cheng: Shanxi Academy of Advanced Research and Innovation
Songzhe Wu: Southeast University
Liqiang Duan: Shanxi Academy of Advanced Research and Innovation
Jihang Zhang: Southeast University
Rong Yin: Nanjing Medical University Affiliated Cancer Hospital
Man Shang: Women’ s Hospital of Nanjing Medical University (Nanjing Women and Children’ s Healthcare Hospital)
Shan Gao: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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-1^28), is expressed in peripheral T cells and tumor infiltrating lymphocytes. PD-1^28 expression is induced on T cells upon activation and is regulated by an RNA binding protein, TAF15. Functionally, PD-1^28 inhibits T cell proliferation, cytokine production, and tumor cell killing in vitro. In vivo, T cell-specific exogenous expression of PD-1^28 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-1^28 functions as an immune checkpoint, and may contribute to resistance to immune checkpoint blockade therapy.

Date: 2024
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DOI: 10.1038/s41467-024-53561-2

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