Targeted activation of melanoma differentiation-associated protein 5 (MDA5) for immunotherapy of pancreatic carcinoma.
The RIG-I-like helicase melanoma differentiation-associated protein 5 (MDA5) is an innate immune receptor for double-stranded viral RNA (dsRNA) that, upon activation, induces a Type I interferon (IFN)-driven immune response. In the present study, we demonstrate that human und murine pancreatic cancer cells express functional MDA5 and are highly sensitive to MDA5-induced cell death. Activation of MDA5 by cytosolic delivery of the synthetic dsRNA analog poly(I:C) led to phosphorylation of the transcription factor IRF3, IFNβ production and upregulation of MHC-I expression. MDA5 signaling also induced tumor cell apoptosis via the intrinsic pathway and sensitized tumor cells toward extrinsic, Fas-mediated apoptosis. Systemic treatment of orthotopic pancreatic cancer-bearing mice with the MDA5 ligand resulted in activated CD8+T cell tumor infiltration, an increased frequency of tumor antigen-specific CD8+T cells and an immunogenic cytokine milieu in the tumor microenvironment. These effects were paralleled by MDA5-induced pronounced tumor cell deathin situand significantly prolonged survival in two different mouse models for pancreatic cancer, an immunotherapeutic response dependent on CD8+T cells. Treated mice were further protected from subsequent tumor challenge. In summary, we identified MDA5 as a novel therapeutic target for overcoming apoptosis resistance and tumor-mediated immunosuppression in pancreatic cancer. MDA5 ligands link innate with adaptive immune mechanisms for effective tumor control.
Abteilung für Klinische Pharmakologie; Medizinische Klinik und Poliklinik IV; Klinikum der Universität München ; Munich, Germany.
Peter
P
Duewell
Abteilung für Klinische Pharmakologie; Medizinische Klinik und Poliklinik IV; Klinikum der Universität München ; Munich, Germany.
Ebba
E
Beller
Abteilung für Klinische Pharmakologie; Medizinische Klinik und Poliklinik IV; Klinikum der Universität München ; Munich, Germany.
Sabrina V
SV
Kirchleitner
Abteilung für Klinische Pharmakologie; Medizinische Klinik und Poliklinik IV; Klinikum der Universität München ; Munich, Germany.
Tina
T
Adunka
Abteilung für Klinische Pharmakologie; Medizinische Klinik und Poliklinik IV; Klinikum der Universität München ; Munich, Germany.
Helene
H
Bourhis
II. Medizinische Klinik; Klinikum rechts der Isar; Technische Universität München ; Munich, Germany.
Jens
J
Siveke
Pathologisches Institut; Ludwig Maximilians Universität ; München, Germany.
Doris
D
Mayr
Abteilung für Klinische Pharmakologie; Medizinische Klinik und Poliklinik IV; Klinikum der Universität München ; Munich, Germany.
Sebastian
S
Kobold
Abteilung für Klinische Pharmakologie; Medizinische Klinik und Poliklinik IV; Klinikum der Universität München ; Munich, Germany.
Stefan
S
Endres
Abteilung für Klinische Pharmakologie; Medizinische Klinik und Poliklinik IV; Klinikum der Universität München ; Munich, Germany.
Max
M
Schnurr
Immunotherapy; MDA5; RIG-I-like helicases; Type I IFN; pancreatic cancer; poly(I:C)