title: Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancies. PDAC builds a tumor microenvironment that plays critical roles in tumor progression and metastasis. However, the relationship between chemotherapy and modulation of PDAC-induced tumor microenvironment remains poorly understood. In this study, we report a role of chemotherapy-derived inflammatory response in the enrichment of PDAC microenvironment with immunosuppressive myeloid cells. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a major cytokine associated with oncogenic KRAS in PDAC cells. GM-CSF production was significantly enhanced in various PDAC cell lines or PDAC tumor tissues from patients after treatment with chemotherapy, which induced the differentiation of monocytes into myeloid-derived suppressor cells (MDSC). Furthermore, blockade of GM-CSF with monoclonal antibodies helped to restore T-cell proliferation when cocultured with monocytes stimulated with tumor supernatants. GM-CSF expression was also observed in primary tumors and correlated with poor prognosis in PDAC patients. Together, these results describe a role of GM-CSF in the modification of chemotherapy-treated PDAC microenvironment and suggest that the targeting of GM-CSF may benefit PDAC patients' refractory to current anticancer regimens by defeating MDSC-mediated immune escape.
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baghdadi
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsuchikawa
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Abe
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nakanishi
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yuu
authors.initials: Y
authors.lastname: Usui
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Mizuna
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Kazuho
authors.initials: K
authors.lastname: Inoko
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Syoki
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Takano
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shichinohe
authors.affiliation: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. seino@igm.hokudai.ac.jp satto@med.hokudai.ac.jp.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Seino
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan. seino@igm.hokudai.ac.jp satto@med.hokudai.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirano
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D016328:NF-kappa B; D003841:Deoxycytidine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005472:Fluorouracil; D000093542:Gemcitabine