Peng, Yang, Antonopoulou, et al. found that in human PDAC, high expression of GATA6 correlated with increased MHC-I expression, immune cell infiltration, and interactions with CD8+ T cells. In murine tumor lines, MEK inhibition (MEKi) further increased MHC-I expression in GATA6high tumor cells, leading to enhanced T cell cytotoxicity against them, while GATA6 knockout or degradation abrogated this effect. In vivo, high GATA6 expression was required for MEKi-induced tumor control, but long-term treatment reduced GATA6+ cells and increased immunosuppressive EMT, which could be overcome by combining MEKi with HDAC inhibitors.
Contributed by Lauren Hitchings
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.
Author Info: (1) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University
Author Info: (1) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. (2) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (3) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (4) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (5) Institute of Biochemistry, University of Kiel, Kiel, Germany. (6) Institute of Biochemistry, University of Kiel, Kiel, Germany. (7) Institute of Biochemistry, University of Kiel, Kiel, Germany. (8) Division Immune Regulation in Cancer, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany. (9) Division Immune Regulation in Cancer, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany. (10) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (11) Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universitt Mnchen, Munich, Germany. (12) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (13) Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universitt Mnchen, Munich, Germany. (14) German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. Department of Urology, West German Cancer Center, University Hospital Essen, Essen, Germany. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (15) German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. Department of Urology, West German Cancer Center, University Hospital Essen, Essen, Germany. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (16) Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (17) Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (18) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (19) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (20) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (21) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (22) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (23) German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany, Department of Diagnostic and Interventional Radiology and Department of Nuclear Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany. (24) Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy. ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. (25) ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. Department of Diagnostics and Public Health, University of Verona, Verona, Italy. (26) EPO - Experimental Pharmacology and Oncology GmbH, Berlin, Germany. (27) Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany. (28) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. f.cheung@dkfz-heidelberg.de. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. f.cheung@dkfz-heidelberg.de. Spatiotemporal tumor heterogeneity, DKTK, partner site Essen, a partnership between DKFZ and University Hospital Essen, Essen, Germany. f.cheung@dkfz-heidelberg.de. (29) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. j.siveke@dkfz.de. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. j.siveke@dkfz.de. National Center for Tumor Diseases (NCT) West, Campus Essen, Essen, Germany. j.siveke@dkfz.de.
