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Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer

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Title: Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer
Authors: Takeuchi, Shintaro Browse this author
Baghdadi, Muhammad Browse this author
Tsuchikawa, Takahiro Browse this author →KAKEN DB
Wada, Haruka Browse this author →KAKEN DB
Nakamura, Toru Browse this author →KAKEN DB
Abe, Hirotake Browse this author
Nakanishi, Sayaka Browse this author
Usui, Yuu Browse this author
Higuchi, Kohtaro Browse this author
Takahashi, Mizuna Browse this author
Inoko, Kazuho Browse this author
Sato, Syoki Browse this author
Takano, Hironobu Browse this author
Shichinohe, Toshiaki Browse this author →KAKEN DB
Seino, Ken-ichiro Browse this author →KAKEN DB
Hirano, Satoshi Browse this author →KAKEN DB
Issue Date: 1-Jul-2015
Publisher: American Association for Cancer Research (AACR)
Journal Title: Cancer research
Volume: 75
Issue: 13
Start Page: 2629
End Page: 2640
Publisher DOI: 10.1158/0008-5472.CAN-14-2921
PMID: 25952647
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.
Description: Supplementary data for this article are available at Cancer Research Online
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Type: article (author version)
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 清野 研一郎

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