MYC- and MIZ1-Dependent Vesicular Transport of Double-Strand RNA Controls Immune Evasion in Pancreatic Ductal Adenocarcinoma.
Bastian Krenz, Anneli Gebhardt-Wolf, Carsten P Ade, Abdallah Gaballa, Florian Roehrig, Emilia Vendelova, Apoorva Baluapuri, Ursula Eilers, Peter Gallant, Luana D'Artista, Armin Wiegering, Georg Gasteiger, Mathias T Rosenfeldt, Stefan Bauer, Lars Zender, Elmar Wolf, Martin Eilers
Author Information
Bastian Krenz: Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany. ORCID
Anneli Gebhardt-Wolf: Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
Carsten P Ade: Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany. ORCID
Abdallah Gaballa: Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany. ORCID
Florian Roehrig: Comprehensive Cancer Center Mainfranken, Core Unit Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany. ORCID
Emilia Vendelova: Institute of Systems Immunology, University of Würzburg, Würzburg, Germany.
Apoorva Baluapuri: Department of Biochemistry and Molecular Biology, Cancer Systems Biology Group, Biocenter, University of Würzburg, Würzburg, Germany. ORCID
Ursula Eilers: Core Unit High-Content Microscopy, Biocenter, University of Würzburg, Würzburg, Germany.
Peter Gallant: Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany. ORCID
Luana D'Artista: Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen, Germany.
Armin Wiegering: Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany. ORCID
Georg Gasteiger: Institute of Systems Immunology, University of Würzburg, Würzburg, Germany. ORCID
Mathias T Rosenfeldt: Institute for Pathology, University of Würzburg, Würzburg, Germany.
Stefan Bauer: Institute for Immunology, BMFZ, Philipps-University of Marburg, Marburg, Germany.
Lars Zender: Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen, Germany.
Elmar Wolf: Department of Biochemistry and Molecular Biology, Cancer Systems Biology Group, Biocenter, University of Würzburg, Würzburg, Germany. ORCID
Martin Eilers: Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany. martin.eilers@biozentrum.uni-wuerzburg.de.
Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRAS and TP53 from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC. SIGNIFICANCE: This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.
