Journal
MOLECULAR CELL
Volume 65, Issue 4, Pages 730-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.01.021
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Funding
- Cancer Research UK program grant [A17341]
- Wellcome Trust [096831/Z/11/Z]
- ERC [294880]
- CRUK Centre grant [515818]
- CRUK Centre Network Accelerator Award on Cancer Immunotherapy (CITA) [525877]
- Manchester-UCL CRUK Lung Cancer Centre of Excellence [522434]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Biotechnology and Biological Sciences Research Council [BB/I004580/1, BB/I004580/2] Funding Source: researchfish
- Cancer Research UK [10950, 22246, 17341] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [20265] Funding Source: researchfish
- Wellcome Trust [096831/Z/11/A] Funding Source: researchfish
- European Research Council (ERC) [294880] Funding Source: European Research Council (ERC)
- BBSRC [BB/I004580/1, BB/I004580/2] Funding Source: UKRI
- Wellcome Trust [096831/Z/11/A] Funding Source: Wellcome Trust
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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.
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