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DDX18 drives tumor immune escape through transcription-activated STAT1 expression in pancreatic cancer

Guoying Dong1, Qin Wang2, Mingxin Wen1

  • 1Department of Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.

Oncogene
|August 24, 2023
PubMed

Insights

Pancreatic cancer (PDAC) shows distinct chromatin changes, with DDX18 (DEAD-box RNA helicase 18) upregulation linked to poor survival. Inhibiting the DDX18-STAT1 pathway offers a novel therapeutic strategy for PDAC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to treatment due to tumor heterogeneity, cancer stem cell survival, and immune evasion within an immunosuppressive tumor microenvironment (TME).
  • Distinct chromatin remodeling occurs in PDAC compared to adjacent tissues, suggesting epigenetic alterations contribute to disease progression.

Purpose of the Study:

  • To investigate the role of DEAD-box RNA helicase 18 (DDX18) in PDAC pathogenesis and its potential as a therapeutic target.
  • To elucidate the molecular mechanisms by which DDX18 influences STAT1 expression, PD-L1 levels, and the tumor immune microenvironment.

Main Methods:

  • Multiple omics analyses (genomics, epigenomics, transcriptomics) were employed to identify key molecular players in PDAC.
  • Chromatin immunoprecipitation (ChIP) assays were used to determine DDX18 and H3K27me3 deposition at the STAT1 promoter.
  • Inhibition of the DDX18-STAT1 axis was assessed in combination with anti-PD-L1 therapy in preclinical models.

Main Results:

  • DDX18 is upregulated in PDAC and correlates with poor patient survival.
  • DDX18 promotes STAT1 expression by counteracting H3K27me3 deposition at the STAT1 promoter, modulating PRC2 complex formation.
  • The DDX18-STAT1 axis enhances cancer stemness, upregulates PD-L1, and contributes to an immunosuppressive TME, characterized by T lymphocyte accumulation and overactivation.
  • Inhibition of the DDX18-STAT1 axis, combined with anti-PD-L1 therapy, led to sustained remission in aggressive PDAC models.

Conclusions:

  • DDX18 is a key driver in PDAC, promoting tumor progression and immune evasion through the DDX18-STAT1-PD-L1 axis.
  • Targeting the DDX18-STAT1 pathway offers a promising strategy to overcome treatment resistance in PDAC.
  • Combination therapy involving DDX18 inhibition and anti-PD-L1 immunotherapy presents a novel clinical approach for treating PDAC patients.

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