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

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Programmed cell death 1 (PD-1) is a key immune checkpoint receptor that regulates T cell responses and is crucial in cancer immune evasion.
• The role of alternative splicing isoforms of PD-1 in cancer immunity and immune escape remains largely unexplored.

Purpose of the Study:

• To identify and characterize novel PD-1 splicing isoforms involved in immune regulation.
• To investigate the functional role of a newly identified PD-1 isoform (PD-1^28) in T cell function and tumor growth.

Main Methods:

• Identification of PD-1 splicing isoforms using molecular biology techniques.
• Analysis of PD-1^28 expression in T cells and tumor-infiltrating lymphocytes.
• In vitro functional assays to assess the impact of PD-1^28 on T cell proliferation, cytokine production, and cytotoxic activity.
• In vivo studies using syngeneic mouse tumor models and humanized NOG mice to evaluate the effect of PD-1^28 on tumor growth.

Main Results:

• An alternative splicing isoform of human PD-1, termed PD-1^28, was identified, featuring a 28-base pair extension from intron 2.
• PD-1^28 is expressed in peripheral T cells and tumor-infiltrating lymphocytes, with its expression induced upon T cell activation and regulated by TAF15.
• In vitro, PD-1^28 significantly inhibited T cell proliferation, cytokine production, and tumor cell killing.
• In vivo, T cell-specific expression of PD-1^28 promoted tumor growth in mouse models, including those with human lung cancer cells.

Conclusions:

• The PD-1^28 isoform functions as an immune checkpoint, suppressing T cell-mediated anti-tumor immunity.
• PD-1^28 may represent a novel mechanism of cancer immune escape.
• This isoform could potentially contribute to resistance against existing immune checkpoint blockade therapies, suggesting it as a therapeutic target.