title: Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing.
abstract: Innate immune sensing of dying cells is modulated by several signals. Inflammatory chemokines-guided early recruitment, and pathogen-associated molecular patterns-triggered activation, of major anti-pathogenic innate immune cells like neutrophils distinguishes pathogen-infected stressed/dying cells from sterile dying cells. However, whether certain sterile dying cells stimulate innate immunity by partially mimicking pathogen response-like recruitment/activation of neutrophils remains poorly understood. We reveal that sterile immunogenic dying cancer cells trigger (a cell autonomous) pathogen response-like chemokine (PARC) signature, hallmarked by co-release of CXCL1, CCL2 and CXCL10 (similar to cells infected with bacteria or viruses). This PARC signature recruits preferentially neutrophils as first innate immune responders in vivo (in a cross-species, evolutionarily conserved manner; in mice and zebrafish). Furthermore, key danger signals emanating from these dying cells, that is, surface calreticulin, ATP and nucleic acids stimulate phagocytosis, purinergic receptors and toll-like receptors (TLR) i.e. TLR7/8/9-MyD88 signaling on neutrophil level, respectively. Engagement of purinergic receptors and TLR7/8/9-MyD88 signaling evokes neutrophil activation, which culminates into H2O2and NO-driven respiratory burst-mediated killing of viable residual cancer cells. Thus sterile immunogenic dying cells perform 'altered-self mimicry' in certain contexts to exploit neutrophils for phagocytic targeting of dead/dying cancer cells and cytotoxic targeting of residual cancer cells.
authors.affiliation: Cell Death Research & Therapy (CDRT) Lab, Department for Cellular and Molecular Medicine, KU Leuven University of Leuven, Leuven, Belgium.|Petri Salven Lab, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Abhishek D
authors.initials: AD
authors.lastname: Garg
authors.affiliation: Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven University of Leuven, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Vandenberk
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Shentong
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Tekele
authors.initials: T
authors.lastname: Fasche
authors.affiliation: Cell Death Research & Therapy (CDRT) Lab, Department for Cellular and Molecular Medicine, KU Leuven University of Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Van Eygen
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical Sciences, KU Leuven University of Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Maes
authors.affiliation: Research Group Experimental Neurosurgery and Neuroanatomy, KU Leuven University of Leuven, Leuven, Belgium.|Laboratoire de Pharmacie Galenique et de Biopharmacie, ULB, Brussels, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: Van Woensel
authors.affiliation: Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven University of Leuven, Leuven, Belgium.
authors.forename: Carolien
authors.initials: C
authors.lastname: Koks
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical Sciences, KU Leuven University of Leuven, Leuven, Belgium.
authors.forename: Niels
authors.initials: N
authors.lastname: Vanthillo
authors.affiliation: Department of Pediatric Oncology and Hematology, Medical School, Saarland University, Homburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Graf
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical Sciences, KU Leuven University of Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: de Witte
authors.affiliation: Immunologisch Onkologisches Zentrum Koln (IOZK), Cologne, Germany.
authors.forename: Stefaan
authors.initials: S
authors.lastname: Van Gool
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Salven
authors.affiliation: Cell Death Research & Therapy (CDRT) Lab, Department for Cellular and Molecular Medicine, KU Leuven University of Leuven, Leuven, Belgium.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics* / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics* / Q000276:immunology; D054357:Chemokine CXCL10 / Q000235:genetics* / Q000276:immunology; D019742:Chemokines, CC / Q000235:genetics* / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D009457:Neuroglia / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D015027:Zebrafish
chemical_list: C111792:CCL18 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D019742:Chemokines, CC; D053594:Myeloid Differentiation Factor 88; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7