Journal Article

DKFZ-2026-00307

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Combined targeted and epigenetic-based therapy enhances antitumor immunity by stabilizing GATA6-dependent MHCI expression in pancreatic ductal adenocarcinoma.

Peng, J.DKFZ* ; Yang, J.DKFZ* ; Antonopoulou, G.DKFZ* ; Fang, R.DKFZ* ; Adhikari, B. ; Vogt, M. ; Wolf, E. ; Sun, C.DKFZ* ; Du, S.DKFZ* ; Godfrey, L.DKFZ* ; Gupta, A. ; Trajkovic-Arsic, M.DKFZ* ; Teichmann, N. ; Grünwald, B. T.DKFZ* ; Krebs, N.DKFZ* ; Steiger, K.DKFZ* ; Mogler, C.DKFZ* ; Althoff, K.DKFZ* ; Wang, X.DKFZ* ; Giglio, G.DKFZ* ; Liffers, S.-T.DKFZ* ; Savvatakis, K.DKFZ* ; Braren, R.DKFZ* ; Lawlor, R. T. ; Scarpa, A. ; Behrens, D. ; Lang, K. S. ; Cheung, P. F.DKFZ* ; Siveke, J.DKFZ*

2026
Springer Nature [London]

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 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.

Note: 2026 Feb 6;17(1):1476 / #DKTKZFB26# / #NCTZFB9#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)
2. NWG Krebs-Immunregulation (D250)
3. DKTK Koordinierungsstelle München (MU01)
4. Koordinierungsstelle NCT West (WT01)
5. DKTK ED Translationale Onkologie Solider Tumore (ED04)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2026

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