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<p>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. Using complementary genetic and pharmacologic approaches, we demonstrate that targeting EREG enhances the sensitivity of quiescent tumor cells and PDAC tumors to CAR T-cell therapy, resulting in reduced relapse and improved overall survival. These findings support a model in which rare quiescent tumor cells contribute to remodeling of the PDAC tumor microenvironment through EREG-associated signaling and suggest that EREG inhibition may enhance the efficacy of adoptive cellular immunotherapy in this disease.</p>

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Quiescent tumor cells shape the immunosuppressive microenvironment in pancreatic cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • B. McClellan,
  • Q. Wang,
  • K. Aung,
  • W. Matsui

摘要

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. Using complementary genetic and pharmacologic approaches, we demonstrate that targeting EREG enhances the sensitivity of quiescent tumor cells and PDAC tumors to CAR T-cell therapy, resulting in reduced relapse and improved overall survival. These findings support a model in which rare quiescent tumor cells contribute to remodeling of the PDAC tumor microenvironment through EREG-associated signaling and suggest that EREG inhibition may enhance the efficacy of adoptive cellular immunotherapy in this disease.