Daisuke Imai1, Tomoharu Yoshizumi2, Shinji Okano1, Shinji Itoh1, Toru Ikegami1, Noboru Harada1, Shinichi Aishima3, Yoshinao Oda4, Yoshihiko Maehara1. 1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 2. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: yosizumi@surg2.med.kyushu-u.ac.jp. 3. Department of Pathology and Microbiology, Saga Medical School Faculty of Medicine, Saga University, Saga, Japan. 4. Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abstract
BACKGROUND: Tumor immune reactions not only provide host defense but also accelerate tumor immune escape and phenotype switching. Here, we examined the association of programmed cell death ligand 1 (PD-L1) expression with epithelial-mesenchymal transition (EMT)-associated markers in pancreatic ductal adenocarcinoma (PDA) within the context of the tumor microenvironment. MATERIALS AND METHODS: PDA samples from 36 patients were analyzed for PD-L1, vimentin, E-cadherin, and Snail expressions and for PDA cell and immune cell infiltration. PD-L1 expression and EMT in PDA cell lines under conditions of altering interferon gamma (IFN-γ) signals were also assessed. RESULTS: Immunohistochemistry revealed a significant correlation between vimentin and PD-L1 expression, whereas double staining showed them to be simultaneously expressed by PDA cells. Positive vimentin expression was associated with the infiltration of a lower number of CD8+ T cells and a higher number of FoxP3+ cells and poor patient prognosis (P = 0.03). PDA tumor cells promoted PD-L1 expression and EMT under the presence of IFN-γ, which was inhibited by the signal transducer and activator of transcription (STAT)1 small interfering RNA. CONCLUSIONS: Strong correlations were observed between PD-L1 expression, EMT, and the immunosuppressive tumor microenvironment. Targeting STAT1 combined with PD-1/PD-L1 immunotherapy may improve outcomes for patients with PDA.
BACKGROUND:Tumor immune reactions not only provide host defense but also accelerate tumor immune escape and phenotype switching. Here, we examined the association of programmed cell death ligand 1 (PD-L1) expression with epithelial-mesenchymal transition (EMT)-associated markers in pancreatic ductal adenocarcinoma (PDA) within the context of the tumor microenvironment. MATERIALS AND METHODS: PDA samples from 36 patients were analyzed for PD-L1, vimentin, E-cadherin, and Snail expressions and for PDA cell and immune cell infiltration. PD-L1 expression and EMT in PDA cell lines under conditions of altering interferon gamma (IFN-γ) signals were also assessed. RESULTS: Immunohistochemistry revealed a significant correlation between vimentin and PD-L1 expression, whereas double staining showed them to be simultaneously expressed by PDA cells. Positive vimentin expression was associated with the infiltration of a lower number of CD8+ T cells and a higher number of FoxP3+ cells and poor patient prognosis (P = 0.03). PDA tumor cells promoted PD-L1 expression and EMT under the presence of IFN-γ, which was inhibited by the signal transducer and activator of transcription (STAT)1 small interfering RNA. CONCLUSIONS: Strong correlations were observed between PD-L1 expression, EMT, and the immunosuppressive tumor microenvironment. Targeting STAT1 combined with PD-1/PD-L1 immunotherapy may improve outcomes for patients with PDA.
Authors: Arik Bernard Schulze; Georg Evers; Dennis Görlich; Michael Mohr; Alessandro Marra; Ludger Hillejan; Jan Rehkämper; Lars Henning Schmidt; Birthe Heitkötter Journal: J Thorac Dis Date: 2020-05 Impact factor: 3.005
Authors: Annika C Betzler; Marie-Nicole Theodoraki; Patrick J Schuler; Johannes Döscher; Simon Laban; Thomas K Hoffmann; Cornelia Brunner Journal: Int J Mol Sci Date: 2020-05-31 Impact factor: 5.923