title: Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response.
abstract: Radiotherapy induces DNA damage and cell death, but recent data suggest that concomitant immune stimulation is an integral part of the therapeutic action of ionizing radiation. It is poorly understood how radiotherapy supports tumor-specific immunity. Here we report that radiotherapy induced tumor cell death and transiently activated complement both in murine and human tumors. The local production of pro-inflammatory anaphylatoxins C3a and C5a was crucial to the tumor response to radiotherapy and concomitant stimulation of tumor-specific immunity. Dexamethasone, a drug frequently given during radiotherapy, limited complement activation and the anti-tumor effects of the immune system. Overall, our findings indicate that anaphylatoxins are key players in radiotherapy-induced tumor-specific immunity and the ensuing clinical responses.
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Surace
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Veronika
authors.initials: V
authors.lastname: Lysenko
authors.affiliation: Department of Radio-Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Andrea Orlando
authors.initials: AO
authors.lastname: Fontana
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Virginia
authors.initials: V
authors.lastname: Cecconi
authors.affiliation: Division Cell Biology II, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Antonela
authors.initials: A
authors.lastname: Bicvic
authors.affiliation: ID Scientific IT Services, Swiss Federal Institute for Technology (ETH), Weinbergstrasse 11, 8092 Zurich, Switzerland.
authors.forename: Michal
authors.initials: M
authors.lastname: Okoniewski
authors.affiliation: Department of Radio-Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Pruschy
authors.affiliation: Department of Dermatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Division Cell Biology II, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.affiliation: Clinic of Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Knuth
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Anurag
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: vandenbroek@immunology.uzh.ch.
authors.forename: Maries
authors.initials: M
authors.lastname: van den Broek
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D003167:Complement Activation; D015926:Complement C3a / Q000235:genetics / Q000276:immunology*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000528:radiation effects*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy; D047368:Tumor Burden / Q000528:radiation effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011951:Receptors, Complement; D003907:Dexamethasone; D015926:Complement C3a; D015936:Complement C5a