Quiescent tumor cells shape the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma

Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, has limited activity in pancreatic ductal adenocarcinoma (PDAC). Using orthotopic PDAC mouse models, we identified a rare population of quiescent PDAC cells that increases after CAR-T cell therapy and exhibits relatively higher clonogenic growth and self-renewal potential than bulk tumor cells. These quiescent cells express high levels of Epiregulin (EREG), a secreted ligand for EGFR and ErbB4, and induce an immunosuppressive tumor microenvironment by increasing the frequency of ErbB4-expressing tumor-associated macrophages. Silencing EREG expression increased the sensitivity of both quiescent cells and tumors to CAR-T cells and improved relapse rates and overall survival. These findings demonstrate that rare quiescent tumor cells can modulate the tumor microenvironment in PDAC and suggest that EREG inhibition may enhance the efficacy of adoptive immunotherapeutic approaches in this disease.