title: Radiotherapy Combined with Novel STING-Targeting Oligonucleotides Results in Regression of Established Tumors.
abstract: Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor-associated antigens. However, the tumor microenvironment into which these antigens are released is typically immunosuppressed, blunting the ability to initiate immune responses. Recently, activation of the DNA sensor molecule STING by cyclic dinucleotides was shown to stimulate infection-related inflammatory pathways in tumors. In this study, we report that the inflammatory pathways activated by STING ligands generate a powerful adjuvant activity for enhancing adaptive immune responses to tumor antigens released by radiotherapy. In a murine model of pancreatic cancer, we showed that combining CT-guided radiotherapy with a novel ligand of murine and human STING could synergize to control local and distant tumors. Mechanistic investigations revealed T-cell-independent and TNFα-dependent hemorrhagic necrosis at early times, followed by later CD8 T-cell-dependent control of residual disease. Clinically, STING was found to be expressed extensively in human pancreatic tumor and stromal cells. Our findings suggest that this novel STING ligand could offer a potent adjuvant for leveraging radiotherapeutic management of pancreatic cancer.
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Baird
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon.
authors.forename: David
authors.initials: D
authors.lastname: Friedman
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cottam
authors.affiliation: Aduro Biotech, Inc., Berkeley, California.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
authors.affiliation: Aduro Biotech, Inc., Berkeley, California.
authors.forename: David B
authors.initials: DB
authors.lastname: Kanne
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Shelly
authors.initials: S
authors.lastname: Bambina
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon.
authors.forename: Keith
authors.initials: K
authors.lastname: Bahjat
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon. The Oregon Clinic, Portland, Oregon.
authors.forename: Marka R
authors.initials: MR
authors.lastname: Crittenden
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon. michael.gough@providence.org.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gough
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D011897:Random Allocation; D059016:Tumor Microenvironment; D000099197:STING Protein
chemical_list: D008565:Membrane Proteins; D009841:Oligonucleotides; C530855:Sting1 protein, mouse; D000099197:STING Protein