The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2

被引：200

作者：

Hartwig, Torsten ^{[1
]}

Montinaro, Antonella ^{[1
]}

von Karstedt, Silvia ^{[1
]}

Sevko, Alexandra ^{[1
]}

Surinova, Silvia ^{[1
]}

Chakravarthy, Ankur ^{[2
]}

Taraborrelli, Lucia ^{[1
]}

Draber, Peter ^{[1
]}

Lafont, Elodie ^{[1
]}

Vargas, Frederick Arce ^{[3
]}

El-Bahrawy, Mona A. ^{[4
]}

Quezada, Sergio A. ^{[3
]}

Walczak, Henning ^{[1
]}

机构：

[1] UCL, UCL Canc Inst, Dept Canc Biol, Ctr Cell Death Canc & Inflammat, London WC1E 6DD, England

[2] UCL, UCL Canc Inst, Dept Oncol, London WC1E 6DD, England

[3] UCL, UCL Canc Inst, Dept Haematol, Canc Immunol Unit, London WC1E 6DD, England

[4] Imperial Coll London, Dept Histopathol, London W12 0NN, England

来源：

MOLECULAR CELL | 2017年 / 65卷 / 04期

基金：

欧洲研究理事会; 英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

NF-KAPPA-B; CELL LUNG-CANCER; SUPPRESSOR-CELLS; TUMORICIDAL ACTIVITY; EXPRESSION; APOPTOSIS; LIGAND; DEATH; FADD; INFLAMMATION;

D O I：

10.1016/j.molcel.2017.01.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Tumor necrosis factor (TNF)-related apoptosisinducing 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-Rmediated 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.

引用

页码：730 / +

页数：18

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