1. Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival
- Author
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Özdemir, Berna C, Pentcheva-Hoang, Tsvetelina, Carstens, Julienne L, Zheng, Xiaofeng, Wu, Chia-Chin, Simpson, Tyler R, Laklai, Hanane, Sugimoto, Hikaru, Kahlert, Christoph, Novitskiy, Sergey V, De Jesus-Acosta, Ana, Sharma, Padmanee, Heidari, Pedram, Mahmood, Umar, Chin, Lynda, Moses, Harold L, Weaver, Valerie M, Maitra, Anirban, Allison, James P, LeBleu, Valerie S, and Kalluri, Raghu
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Rare Diseases ,Digestive Diseases ,Pancreatic Cancer ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Carcinoma ,Pancreatic Ductal ,Disease Models ,Animal ,Fibroblasts ,Fibrosis ,Humans ,Immune Tolerance ,Mice ,Mice ,Transgenic ,Pancreatic Neoplasms ,Survival Analysis ,Neurosciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - 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.
- Published
- 2014