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

Intratumoral heterogeneity underlies therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC). GATA6 plays pivotal role in regulating tumor cell plasticity in the classical subtype of PDAC. Here we investigated the immune features of GATA6+ tumor cells and exploited targeting strategies to enhance GATA6-dependent anti-tumor immune responses using preclinical PDAC models. Our findings revealed a positive correlation between GATA6 tumor expression and the presence of CD4+, FOXP3+, CD20+, and tumor-infiltrating CD8+ cells in human PDAC. Through cell-cell communication analysis and multiplex tissue imaging, we confirm strong spatial interactions between GATA6+ tumor cells and immune cells. Transcriptomic profiling of murine PDAC cell lines during pharmacological MAPK inhibition (MEKi) shows a specific enrichment of antigenicity-related gene sets in GATA6+ cancer cells. Targeted GATA6 degradation with an auxin-inducible degron knock-in in murine PDAC cells significantly diminished MEKi-induced MHCI and IFNγ expression. Functional effect of GATA6+ tumor cell-specific MHCI upregulation was confirmed by co-culturing murine PDAC carrying LCMV-gp33 as model antigen with cytotoxic gp33-TCR transgenic T cells in the presence of MEKi. In patient-derived xenografts and genetic mouse models of spontaneous PDAC, MEKi transiently boosted tumor MHCI expression in GATA6+ tumors, which was subsequently reduced upon a treatment-induced mesenchymal state switch. In vivo combined MAPH and HDAC inhibition with trametinib and domatinostat effectively restored GATA6+ tumor cell populations with increased MHCI, resulting in enhanced cytotoxic T cell infiltration, reduced tumor growth and improved survival. Multiplex spatial analysis confirmed higher MHCI expression in GATA6+ tumor cells sensitized to T cell cytotoxicity. We identified a GATA6-dependent MHCI upregulation in tumor cells upon MEKi, which is counterbalanced by a treatment-induced cell state switch. Combination MEKi with HDACi retained the responsive GATA6+ tumor population, proposing this combination therapy to potentiate immune-based anti-tumor responses.