title: RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells.
abstract: Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8α(+) DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8(+) T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity.
authors.affiliation: 1] Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany [2] Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Duewell
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Steger
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Lohr
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Bourhis
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Hoelz
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: S V
authors.initials: SV
authors.lastname: Kirchleitner
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: M R
authors.initials: MR
authors.lastname: Stieg
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Grassmann
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kobold
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: J T
authors.initials: JT
authors.lastname: Siveke
authors.affiliation: Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Endres
authors.affiliation: 1] Abteilung für Klinische Pharmakologie and Center for Integrated Protein Science Munich (CIPS M), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany [2] Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, München, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schnurr
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D045142:Cross-Priming; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007167:Immunotherapy; D058847:Inflammasomes / Q000378:metabolism; D007370:Interferon Type I / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D007370:Interferon Type I; D051193:Toll-Like Receptors; D053487:DEAD-box RNA Helicases