Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer

• Published in: Biochimica et biophysica acta. Molecular cell research 2017-05, Vol.1864 (5), p.782-796
• Main Authors: Geismann, Claudia, Grohmann, Frauke, Dreher, Anita, Häsler, Robert, Rosenstiel, Philip, Legler, Karen, Hauser, Charlotte, Egberts, Jan Hendrik, Sipos, Bence, Schreiber, Stefan, Linkermann, Andreas, Hassan, Zonera, Schneider, Günter, Schäfer, Heiner, Arlt, Alexander
• Format: Article
• Language: English
• Subjects: Adult; Animals; Apoptosis resistance; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - pathology; CCL20; Cells, Cultured; Chemokine CCL20 - antagonists & inhibitors; Chemokine CCL20 - genetics; Chemokine CCL20 - physiology; Chemotaxis, Leukocyte - drug effects; Chemotaxis, Leukocyte - genetics; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - immunology; Humans; Lymphocytes - drug effects; Lymphocytes - physiology; Mice; Mice, Transgenic; NF-kappa B - metabolism; NF-κB; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; RNA, Small Interfering - pharmacology; TNF-Related Apoptosis-Inducing Ligand - therapeutic use; TRAIL
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2017.02.005

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers. From a clinical view, the transcription factor NF-κB is of particular importance, since this pathway confers apoptosis resistance and limits drug efficacy. Whereas the role of the most abundant NF-κB subunit p65/RelA in therapeutic resistance is well documented, only little knowledge of the RelA downstream targets and their functional relevance in TRAIL mediated apoptosis in PDAC is available. In the present study TRAIL resistant and sensitive PDAC cell lines were analyzed for differentially expressed RelA target genes, to define RelA downstream targets mediating TRAIL resistance. The most upregulated target gene was then further functionally characterized. Unbiased genome-wide expression analysis demonstrated that the chemokine CCL20 represents the strongest TRAIL inducible direct RelA target gene in resistant PDAC cells. Unexpectedly, targeting CCL20 by siRNA, blocking antibodies or by downregulation of the sole CCL20 receptor CCR6 had no effect on PDAC cell death or cancer cell migration, arguing against an autocrine role of CCL20 in PDAC. However, by using an ex vivo indirect co-culture system we were able to show that CCL20 acts paracrine to recruit immune cells. Importantly, CCL20-recruited immune cells further increase TRAIL resistance of CCL20-producing PDAC cells. In conclusion, our data show a functional role of a RelA-CCL20 pathway in PDAC TRAIL resistance. We demonstrate how the therapy-induced cross-talk of cancer cells with immune cells affects treatment responses, knowledge needed to tailor novel bi-specific treatments, which target tumor cell as well as immune cells. [Display omitted] •human co-culture models allowed us to decipher the role of CCL20 in apoptosis resistance.•Paracrine acting CCL20 attracts immune cells, which secondary mediate resistance against death receptors.•targeting NF-κB mediated apoptosis resistance, demand to address the tumor and the immune cells.