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

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...

Full description

Saved in:
Bibliographic Details
Published in:Molecular cell 2017-02, Vol.65 (4), p.730-742.e5
Main Authors: Hartwig, Torsten, Montinaro, Antonella, von Karstedt, Silvia, Sevko, Alexandra, Surinova, Silvia, Chakravarthy, Ankur, Taraborrelli, Lucia, Draber, Peter, Lafont, Elodie, Arce Vargas, Frederick, El-Bahrawy, Mona A., Quezada, Sergio A., Walczak, Henning
Format: Article
Language:English
Subjects:
A549 Cells
Adenocarcinoma - genetics
Adenocarcinoma - immunology
Adenocarcinoma - metabolism
Adenocarcinoma - pathology
Adenocarcinoma of Lung
Animals
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - immunology
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - pathology
Caspase 8 - genetics
Caspase 8 - metabolism
CCL2
CCR2
Cell Proliferation
Chemokine CCL2 - metabolism
cytokine
Cytokines - metabolism
FADD
Fas-Associated Death Domain Protein - genetics
Fas-Associated Death Domain Protein - metabolism
Female
HCT116 Cells
HeLa Cells
Humans
Lung Neoplasms - genetics
Lung Neoplasms - immunology
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Macrophages - immunology
Macrophages - metabolism
Macrophages - pathology
MDSC
Mice, Inbred C57BL
Mice, SCID
microenvironment
Phenotype
Receptors, CCR2 - metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism
RNA Interference
Signal Transduction
Time Factors
TNF-Related Apoptosis-Inducing Ligand - metabolism
TRAIL
TRAIL-R
Transfection
tumor
Tumor Burden
Tumor Microenvironment
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
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. [Display omitted] •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 Hartwig et al. show that endogenous TRAIL signaling in cancer cells induces a FADD-dependent secretome that promotes the accumulation of M2-like immune cells and tumor growth via host CCR2.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2017.01.021