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<p>GATA6 promotes epithelial phenotypes and limits epithelial-to-mesenchymal (EMT) transition in pancreatic ductal adenocarcinoma (PDAC). Here we show that GATA6 defines a tumor cell state that induces MHCI expression and anti-tumor cytotoxicity upon therapy. In human PDAC, GATA6 expression correlates with immune cell infiltration, and spatial analysis reveals interaction between GATA6<sup>+</sup> tumor cells and CD8<sup>+</sup> T cells. In murine PDAC, MEK inhibition (MEKi) enriches antigenicity-related gene sets in GATA6<sup>high</sup> cells, while GATA6 knockout or degradation impairs MEKi-induced MHCI upregulation. High-GATA6 tumors respond to MEKi with increased MHCI, enhancing T-cell cytotoxicity, whereas GATA6 loss abolishes this effect. Treatment-induced EMT reduces GATA6<sup>+</sup> populations and MHCI expression, which is restored by combining MEKi with HDAC inhibitors, enhancing GATA6<sup>+</sup> tumor cells, MHCI, CD8<sup>+</sup> T cell infiltration, tumor suppression, and survival. These findings suggest that therapeutic strategies promoting a GATA6-driven tumor cell state improve immune recognition of PDAC cells and potentiate anti-tumor cytotoxic effects.</p>

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Combined targeted and epigenetic-based therapy enhances antitumor immunity by stabilizing GATA6-dependent MHCI expression in pancreatic ductal adenocarcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月6日

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  • JuanFei Peng,
  • JiaJin Yang,
  • Georgia Antonopoulou,
  • Rui Fang,
  • Bikash Adhikari,
  • Markus Vogt,
  • Elmar Wolf,
  • Chong Sun,
  • Shangce Du,
  • Laura Godfrey,
  • Aayush Gupta,
  • Marija Trajkovic-Arsic,
  • Nicole Teichmann,
  • Barbara T. Grünwald,
  • Niklas Krebs,
  • Katja Steiger,
  • Carolin Mogler,
  • Kristina Althoff,
  • Xin Wang,
  • Giovanni Giglio,
  • Sven-Thorsten Liffers,
  • Konstantinos Savvatakis,
  • Rickmer Braren,
  • Rita T. Lawlor,
  • Aldo Scarpa,
  • Diana Behrens,
  • Karl S. Lang,
  • Phyllis F. Cheung,
  • Jens T. Siveke

摘要

GATA6 promotes epithelial phenotypes and limits epithelial-to-mesenchymal (EMT) transition in pancreatic ductal adenocarcinoma (PDAC). Here we show that GATA6 defines a tumor cell state that induces MHCI expression and anti-tumor cytotoxicity upon therapy. In human PDAC, GATA6 expression correlates with immune cell infiltration, and spatial analysis reveals interaction between GATA6+ tumor cells and CD8+ T cells. In murine PDAC, MEK inhibition (MEKi) enriches antigenicity-related gene sets in GATA6high cells, while GATA6 knockout or degradation impairs MEKi-induced MHCI upregulation. High-GATA6 tumors respond to MEKi with increased MHCI, enhancing T-cell cytotoxicity, whereas GATA6 loss abolishes this effect. Treatment-induced EMT reduces GATA6+ populations and MHCI expression, which is restored by combining MEKi with HDAC inhibitors, enhancing GATA6+ tumor cells, MHCI, CD8+ T cell infiltration, tumor suppression, and survival. These findings suggest that therapeutic strategies promoting a GATA6-driven tumor cell state improve immune recognition of PDAC cells and potentiate anti-tumor cytotoxic effects.