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Molecular cell v.65 no.4, 2017년, pp.730 - 742.e5   SCI SCIE
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The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2

Hartwig, Torsten (Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK ) ; Montinaro, Antonella (Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK ) ; von Karstedt, Silvia (Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK ) ; Sevko, Alexandra (Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK ) ; Surinova, Silvia (Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK ) ; Chakravarthy, Ankur (Department of Oncology, UCL Cancer Institute, University College London, London WC1E 6DD, UK ) ; Taraborrelli, Lucia (Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK ) ; Draber, Peter (Centr ) ; Lafont, Elodie ; Arce Vargas, Frederick ; El-Bahrawy, Mona A. ; Quezada, Sergio A. ; Walczak, Henning ;
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    Summary Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monocyte polarization to myeloid-derived suppressor cells (MDSCs) and M2-like macrophages. TRAIL-R suppression in tumor cells impaired CCL2 production and diminished both lung MDSC presence and tumor growth. In accordance, the receptor of CCL2, CCR2, is required to facilitate increased MDSC presence and tumor growth. Finally, TRAIL and CCL2 are co-regulated with MDSC/M2 markers in lung adenocarcinoma patients. Collectively, endogenous TRAIL/TRAIL-R-mediated CCL2 secretion promotes accumulation of tumor-supportive immune cells in the cancer microenvironment, thereby revealing a tumor-supportive immune-modulatory role of the TRAIL/TRAIL-R system in cancer biology. Highlights TRAIL induces a cytokine cancer secretome in a FADD- and caspase-8-dependent manner FADD promotes tumor growth along with accumulation of M2-like immune cells in vivo The TRAIL-induced secretome recruits M2-like immune cells to tumors via CCR2 TRAIL/CCL2 correlate with a tumor-supportive immune profile in lung cancer patients Graphical Abstract [DISPLAY OMISSION]


  • 주제어

    TRAIL .   TRAIL-R .   FADD .   cytokine .   CCL2 .   CCR2 .   microenvironment .   MDSC .   tumor.  

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