Abstract A039: Epigenetic regulation of cellular heterogeneity and the tumor-immune landscape in pancreatic cancer

Abstract

Cellular heterogeneity in pancreatic ductal adenocarcinoma (PDAC) poses significant challenges for disease prognosis and limits the effectiveness of therapeutic strategies implemented in recent multicenter subtype-based clinical trials worldwide. A hallmark of PDAC is extensive intratumoral heterogeneity, which is largely driven by the coexistence of two transcriptionally distinct neoplastic states: the therapy-responsive classical (CLA) subtype and the aggressive basal-like (BL) subtype. The relative proportions of these states evolve throughout disease progression and play a crucial role in shaping therapeutic responses and clinical outcome. Increasing evidence indicates that subtype identity is not static but is maintained through dynamic epigenetic regulation. However, the chromatin-level mechanisms that stabilize or destabilize these cellular states remain poorly defined. A particular critical question is how tumor cell-intrinsic epigenetic regulators interact with inflammatory signals from the tumor immune microenvironment (TiME) to sustain subtype plasticity and drive disease progression. Here we identify a regulatory program driven by BRD4 and HDAC1 that operates at the interface of tumor cell identity and immune microenvironmental remodeling. We found that the epigenetic regulators BRD4 and HDAC1 coordinate distinct AP1 transcription factor complexes to stabilize opposing neoplastic states. BRD4-driven cJUN/AP1 activity promotes a BL transcriptional program and establishes an immunosuppressive TiME. In contrast, HDAC1-JUNB/AP1maintains a CLA-like epithelial identity by epigenetically repressing inflammatory programs (e.g. TNF-α signaling). Mechanistically, spatially localized macrophage-derived TNF-α destabilizes the CLA state, thereby generating a feed-forward circuit that sustains subtype coexistence and promotes PDAC aggressiveness. Across independent multi-center patient cohorts, disruption of the HDAC1–JUNB/AP1-dependent epigenetic program in CLA PDAC associates with significantly poorer clinical outcomes. Spatial analysis of patient tumors further reveals that TNF-α-rich niches are characterized by macrophage enrichment and CD8+ T cell exclusion, consistent with an immunosuppressive TiME. Pharmacological inhibition of the BRD4-cJUN/AP1 axis, as well as combined TNF-α blockade with chemotherapy, restores a more favorable immune landscape and improves survival in preclinical models of BL PDAC. Together, these findings define intratumoral subtype heterogeneity as a spatially and epigenetically dynamic process driven by reciprocal interactions between tumor-intrinsic chromatin programs and inflammatory signals within the microenvironment. This work provides a mechanistic framework for subtype-informed therapeutic strategies and highlights combined epigenetic and immune-targeted interventions as a promising avenue for PDAC treatment.