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

  • Cancer Cell. 2014 Jun 16;25(6):719-34. doi: 10.1016/j.ccr.2014.04.005.
Berna C Özdemir  1 ,  Tsvetelina Pentcheva-Hoang  2 ,  Julienne L Carstens  3 ,  Xiaofeng Zheng  3 ,  Chia-Chin Wu  4 ,  Tyler R Simpson  2 ,  Hanane Laklai  5 ,  Hikaru Sugimoto  1 ,  Christoph Kahlert  1 ,  Sergey V Novitskiy  6 ,  Ana De Jesus-Acosta  7 ,  Padmanee Sharma  2 ,  Pedram Heidari  8 ,  Umar Mahmood  8 ,  Lynda Chin  4 ,  Harold L Moses  6 ,  Valerie M Weaver  5 ,  Anirban Maitra  9 ,  James P Allison  2 ,  Valerie S LeBleu  1 ,  Raghu Kalluri  10
Affiliations
  • 1. Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
  • 2. Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 3. Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 4. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 5. Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 6. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 7. Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
  • 8. Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 9. Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 10. Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 24856586 DOI: 10.1016/j.ccr.2014.04.005
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.