Myofibroblasts promote immune surveillance and protect against PDAC growth and invasion.

  • Major finding: Myofibroblasts promote immune surveillance and protect against PDAC growth and invasion.

  • Concept: Myofibroblast depletion enhances PDAC progression by inducing immunosuppression, EMT, and hypoxia.

  • Impact: Targeting of pancreatic cancer–associated fibroblasts should be cautioned in the clinic.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a marked desmoplastic stroma consisting of extracellular matrix proteins and α-smooth muscle actin–positive (αSMA+) myofibroblasts. Although fibrosis has been suggested to impede chemotherapeutic drug delivery, the role of αSMA+ myofibroblasts in PDAC progression remains poorly understood. To address this question, Özdemir and colleagues selectively depleted αSMA+ myofibroblasts in genetically engineered mouse models of PDAC. Myofibroblast depletion initiated either at the onset of pancreatic intraepithelial neoplasia precursor lesions or in established PDAC induced the formation of highly invasive, undifferentiated, and necrotic tumors and decreased survival, suggesting that αSMA+ myofibroblasts inhibit PDAC progression. Of note, low αSMA levels were also correlated with an undifferentiated tumor phenotype and reduced survival in patients with PDAC. Myofibroblast loss did not improve the response of murine PDAC tumors to the chemotherapeutic agent gemcitabine, but resulted in collagen reorganization, reduced vascularity, increased hypoxia, and cancer stem cell–like features. These changes were associated with differential expression of genes involved in extracellular matrix remodeling, epithelial–mesenchymal transition (EMT), angiogenesis, and immune responses. Intriguingly, myofibroblast depletion significantly increased the percentage of forkhead box P3 (FOXP3)–expressing regulatory T cells (Treg) and diminished the percentage of effector T cells (Teff), suggesting that antitumor immune responses are impaired in the absence of fibrosis. Consistent with this idea, inhibition of cytotoxic T-lymphocyte–associated protein 4 (CTLA4) expressed on Treg cells rescued the myofibroblast-depleted tumor phenotype, resulting in restoration of the Teff/Treg ratio, attenuated PDAC progression, and prolonged survival. These results demonstrate that cancer-associated myofibroblasts protect against PDAC growth and progression by stimulating immune surveillance and suggest that patients with increased fibrosis may benefit from anti-CTLA4 immunotherapy. Furthermore, these findings provide evidence that strategies to target cancer-associated fibroblasts in pancreatic cancer should be used with caution.

Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014 May 22 [Epub ahead of print].