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, G Giglio, Sven‐Thorsten Liffers, Konstantinos Savvatakis, Rickmer Braren, Rita T. Lawlor, Aldo Scarpa, Diana Behrens, Karl S. Lang, Phyllis F. Cheung, Jens Siveke
Abstract 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 GATA6 high 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.