Gamma-delta T cells stimulate IL-6 production by pancreatic stellate cells in pancreatic ductal adenocarcinoma
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ORIGINAL ARTICLE – CANCER RESEARCH
Gamma‑delta T cells stimulate IL‑6 production by pancreatic stellate cells in pancreatic ductal adenocarcinoma Adrian M. Seifert1,2 · Julian List1 · Max Heiduk1,3 · Rahel Decker1 · Janusz von Renesse1 · Ann‑Christin Meinecke1 · Daniela E. Aust4,5 · Thilo Welsch1,2 · Jürgen Weitz1,2 · Lena Seifert1,2 Received: 3 July 2020 / Accepted: 18 August 2020 © The Author(s) 2020
Abstract Introduction The immunosuppressive tumor microenvironment promotes progression of pancreatic ductal adenocarcinoma (PDAC). γδ T cells infiltrate the pancreatic tumor stroma and support tumorigenesis through αβ T cell inhibition. Pancreatic stellate cell (PSC) activation contributes to pancreatic fibrosis in PDAC, limiting the delivery and efficacy of therapeutic agents. Whether γδ T cells have direct effects on PSC activation is unknown. Methods In this study, we analyzed tumor tissue from 68 patients with PDAC and determined the frequency and location of γδ T cells using immunohistochemistry and immunofluorescence. PDAC samples from the TCGA database with low and high TRGC2 expression were correlated with the expression of extracellular matrix genes. Further, PSCs were isolated from pancreatic tumor tissue and co-cultured with γδ T cells for 48 hours and cytokine production was measured using a cytometric bead array. Results γδ T cells infiltrated the pancreatic tumor stroma and were located in proximity to PSCs. A high infiltration of γδ T cells was associated with increased expression of several extracellular matrix genes in human PDAC. In vitro, γδ T cells stimulated IL-6 production by PDAC-derived PSCs. Conclusion γδ T cells activated PSCs and modulation of this interaction may enhance the efficacy of combinational therapies in human PDAC. Keywords Pancreatic cancer · Gamma-delta T cells · Pancreatic stellate cells · IL-6
Introduction Adrian M. Seifert and Julian List have contributed to this work equally. * Lena Seifert [email protected] 1
Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany
2
German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Dresden, Heidelberg, Germany
3
National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany
4
Department of Pathology, Medical Faculty, University Hospital Carl Gustav Carus, University of Dresden, Dresden, Germany
5
NCT Biobank Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and projected to become the second leading cause of cancer-related deaths by 2030 (Yadav and Lowenfels 2013). One of the main reasons for its poor prognosis is the extensive fibrotic tumor stroma that impedes successful cancer therapies. Studies employing checkpoint inhibitors in PDAC have failed to elicit a sufficient response, likely due
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