Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival

Berna C. Özdemir, Tsvetelina Pentcheva-Hoang, Julienne L. Carstens, Xiaofeng Zheng, Chia Chin Wu, Tyler R. Simpson, Hanane Laklai, Hikaru Sugimoto, Christoph Kahlert, Sergey V. Novitskiy, Ana DeJesus-Acosta, Padmanee Sharma, Pedram Heidari, Umar Mahmood, Lynda Chin, Harold L. Moses, Valerie M. Weaver, Anirban Maitra, James P. Allison, Valerie S. LeBleuRaghu Kalluri

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.

Original languageEnglish (US)
Pages (from-to)719-734
Number of pages16
JournalCancer cell
Volume25
Issue number6
DOIs
StatePublished - Jun 16 2014

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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