Abstract B075: Epiregulin, a targetable niche-promoting factor, is utilized by quiescent stem-like cells within pancreatic tumors to facilitate resistance to CAR T-cell therapy

Abstract Cancer is typically defined by uncontrolled cellular proliferation; however, tumors also contain slower-cycling cell populations influenced by diverse environmental factors, such as nutrient deprivation, modifications in the extracellular matrix, and inflammatory stimuli. Reversible dormancy or quiescence plays a critical role in tissue and embryonic stem cell function and serves as a protective mechanism against inflammatory injury. In this study, a substantial proportion of quiescent cells, identified via an established live-cell reporter, were enriched from the tumor cell population using adoptive cell therapy models in orthotopic murine pancreatic tumors. These immune-evasive, quiescent cells exhibited increased tumorigenicity, chemoresistance, and stem-like properties. Remarkably, rather than possessing intrinsic resistance, these stem-like cancer cells acquired their immune-evasive capacity by establishing a protective niche within the tumor microenvironment. RNA sequencing of quiescent, immune-evasive cancer cells post-adoptive cell therapy highlighted epiregulin (EREG)—a secreted ligand of EGFR and ERBB4—as one of the most highly upregulated transcripts. Protein and single-cell transcriptomic analyses in humans show that EREG is highly expressed in slow-cycling cells, and its expression correlates with overall survival in patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutic targeting of EREG in multiple murine tumor models resulted in the depletion of quiescent stem-like cells and enhanced outcomes with CAR T-cell therapy. Collectively, these findings identify EREG as a niche factor facilitating quiescent cell evasion of CAR T-cell therapy and indicate that disruption of this niche may enhance immunotherapeutic efficacy in PDAC by depleting quiescent stem-like cells and improving response rates. Citation Format: Bryan McClellan, Qiuju Wang, William Matsui. Epiregulin, a targetable niche-promoting factor, is utilized by quiescent stem-like cells within pancreatic tumors to facilitate resistance to CAR T-cell therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B075.