title: The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2.
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.
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hartwig
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Montinaro
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: von Karstedt
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sevko
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Surinova
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Ankur
authors.initials: A
authors.lastname: Chakravarthy
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Taraborrelli
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Draber
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Elodie
authors.initials: E
authors.lastname: Lafont
authors.affiliation: Cancer Immunology Unit, Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Frederick
authors.initials: F
authors.lastname: Arce Vargas
authors.affiliation: Department of Histopathology, Imperial College London, London W12 0NN, UK.
authors.forename: Mona A
authors.initials: MA
authors.lastname: El-Bahrawy
authors.affiliation: Cancer Immunology Unit, Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6DD, UK. Electronic address: h.walczak@ucl.ac.uk.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010641:Phenotype; D034622:RNA Interference; D054390:Receptors, CCR2 / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D054390:Receptors, CCR2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: CCL2; CCR2; FADD; MDSC; TRAIL; TRAIL-R; cytokine; microenvironment; tumor