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

Mol Cell. 2017 Feb 16;65(4):730-742.e5. doi: 10.1016/j.molcel.2017.01.021.

Abstract

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.

Keywords: CCL2; CCR2; FADD; MDSC; TRAIL; TRAIL-R; cytokine; microenvironment; tumor.

MeSH terms

  • 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
  • Cell Proliferation
  • Chemokine CCL2 / metabolism
  • Cytokines / metabolism*
  • 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
  • Mice, Inbred C57BL
  • Mice, SCID
  • Phenotype
  • RNA Interference
  • Receptors, CCR2 / metabolism*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Time Factors
  • Transfection
  • Tumor Burden
  • Tumor Microenvironment*

Substances

  • CCL2 protein, human
  • CCR2 protein, human
  • Chemokine CCL2
  • Cytokines
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Receptors, CCR2
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • CASP8 protein, human
  • Caspase 8