PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer

Area of Science:

• Molecular Oncology
• Cancer Immunology
• Epigenetics

Background:

• Gallbladder cancer (GBC) is a prevalent biliary malignancy with limited treatment efficacy.
• Aberrant alternative splicing is implicated in tumorigenesis.
• The splicing factor polypyrimidine region-binding protein 3 (PTBP3) is found to be highly expressed in GBC.

Purpose of the Study:

• To investigate the role of PTBP3 in GBC development and immune evasion.
• To elucidate the mechanism by which PTBP3 influences alternative splicing of Interleukin-18 (IL-18).
• To explore potential therapeutic strategies targeting the PTBP3-mediated splicing pathway.

Main Methods:

• Analysis of GEO database and GBC mRNA-seq data.
• Multi-omics analysis to identify splicing alterations and downstream effects.
• In vivo validation using a HuPBMC mouse model.
• Investigation of epigenetic modifications (H3K36me3) and protein interactions (MRG15, SETD2, hnRNPL).

Main Results:

• PTBP3 promotes exon skipping of IL-18, leading to the tumor-specific isoform ΔIL-18.
• ΔIL-18 facilitates GBC immune escape by reducing CD8+ T cell PD-1 degradation via FBXO38 downregulation.
• PTBP3 and ΔIL-18 promote GBC growth; an antisense oligonucleotide targeting ΔIL-18 showed anti-tumor activity.
• H3K36me3 and MRG15 recruit PTBP3 to IL-18 pre-mRNA, coupling transcription and splicing.
• SETD2 interferes with PTBP3 binding to IL-18 pre-mRNA.

Conclusions:

• Aberrant alternative splicing, driven by PTBP3, is a key mechanism in GBC immune escape.
• The PTBP3/ΔIL-18 axis represents a promising therapeutic target for GBC immunotherapy.
• Epigenetic regulation influences alternative splicing in GBC, providing further avenues for research.