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

Takeuchi, Shintaro  ,  Baghdadi, Muhammad  ,  Tsuchikawa, Takahiro  ,  Wada, Haruka  ,  Nakamura, Toru  ,  Abe, Hirotake  ,  Nakanishi, Sayaka  ,  Usui, Yuu  ,  Higuchi, Kohtaro  ,  Takahashi, Mizuna  ,  Inoko, Kazuho  ,  Sato, Syoki  ,  Takano, Hironobu  ,  Shichinohe, Toshiaki  ,  Seino, Ken-ichiro  ,  Hirano, Satoshi

75 ( 13 )  , pp.2629 - 2640 , 2015-07-01 , American Association for Cancer Research (AACR)
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.

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