Posttranscriptional regulation of PD-1 by PRMT5/WDR77 complex shapes T cell effector function and antitumor immunity

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• Programmed cell death protein 1 (PD-1) gene regulation is crucial for T cell function and tumor immune evasion.
• Posttranscriptional mechanisms controlling PD-1 levels remain largely uncharacterized.

Purpose of the Study:

• To elucidate the posttranscriptional regulation of PDCD1 (PD-1 gene).
• To identify novel regulators of PD-1 and their role in T cell-mediated anti-tumor immunity.

Main Methods:

• RNA immunoprecipitation followed by mass spectrometry to identify RNA-binding proteins.
• Quantitative PCR and Western blotting to assess gene and protein expression.
• Conditional knockout mouse models to study in vivo function.
• Analysis of clinical tumor-infiltrating T cells.

Main Results:

• PRMT5 identified as an RNA-binding protein promoting PDCD1 mRNA decay via interaction with WDR77 and Argonaute2.
• Type-I IFN/STAT1 pathway upregulates PRMT5 and WDR77, enhancing their binding to PDCD1 3' UTR.
• Loss of PRMT5 or WDR77 in T cells impairs effector function and increases sensitivity to anti-PD-1 therapy.
• Clinical data shows inverse correlation between PRMT5/WDR77 and PDCD1 expression in tumor-infiltrating T cells, predicting immunotherapy resistance.

Conclusions:

• PRMT5, through RNA-binding activity with WDR77, posttranscriptionally regulates PDCD1 mRNA stability and T cell effector function.
• STAT1-mediated upregulation of PRMT5/WDR77 is a key mechanism for PD-1 regulation.
• Targeting STAT1 with fludarabine in combination with anti-PD-1 therapy shows synergistic anti-tumor effects.