PD-1^IR2 promotes tumor evasion via deregulating CD8⁺ T cell function

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• Programmed cell death 1 (PD-1) is a key immune checkpoint protein that tumors exploit for immune evasion.
• Alternative splicing (AS), including intron retention (IR), influences immune gene processing and function, but its role in PD-1 and tumor evasion is unclear.

Purpose of the Study:

• To identify and characterize an intron retention (IR) splicing isoform of PDCD1 (encoding PD-1).
• To investigate the functional role of this novel PD-1 isoform in T cell-mediated immunity and tumor evasion.

Main Methods:

• Identified and sequenced the PD-1^IR2 isoform using RT-PCR and Sanger sequencing.
• Assessed PD-1^IR2 expression via quantitative RT-PCR and flow cytometry.
• Evaluated PD-1^IR2 function in vitro (T cell proliferation, cytokine secretion, tumor cell killing) and in vivo using PDCD1^IR2 knock-in mice and humanized PBMC-NOG mice.

Main Results:

• PD-1^IR2 is expressed in leukemia cell lines and tumor-infiltrating lymphocytes, induced upon T cell activation, and regulated by hnRNPLL.
• PD-1^IR2 negatively impacts CD8⁺ T cell immune functions, inhibiting proliferation, cytokine production, and tumor cell killing.
• PD-1^IR2 expression in T cells promotes tumor evasion and confers resistance to anti-PD-L1 therapy in mouse models.

Conclusions:

• PD-1^IR2 functions as a novel immune checkpoint that suppresses T cell-mediated antitumor responses.
• This isoform may represent a mechanism of resistance to existing immune checkpoint inhibitor therapies, suggesting it as a potential therapeutic target.