1. Academic Validation
  2. PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer

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

  • Adv Sci (Weinh). 2024 Aug 8:e2406633. doi: 10.1002/advs.202406633.
Cheng Zhao 1 2 Jing-Wei Zhao 1 2 Yu-Han Zhang 2 Yi-di Zhu 1 2 Zi-Yi Yang 1 2 Shi-Lei Liu 1 2 Qiu-Yi Tang 1 2 Yue Yang 1 2 Hua-Kai Wang 1 2 Yi-Jun Shu 1 2 Ping Dong 1 2 Xiang-Song Wu 1 2 Wei Gong 1 2
Affiliations

Affiliations

  • 1 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China.
  • 2 Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
Abstract

Gallbladder Cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.

Keywords

IL‐18; PTBP3; alternative splicing; gallbladder cancer; immune escape.

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