title: Exogenous IL-33 Restores Dendritic Cell Activation and Maturation in Established Cancer.
abstract: The role of IL-33, particularly in tumor growth and tumor immunity, remains ill-defined. We show that exogenous IL-33 can induce robust antitumor effect through a CD8+T cell-dependent mechanism. Systemic administration of rIL-33 alone was sufficient to inhibit growth of established tumors in transplant and de novo melanoma tumorigenesis models. Notably, in addition to a direct action on CD8+T cell expansion and IFN-γ production, rIL-33 therapy activated myeloid dendritic cells (mDCs) in tumor-bearing mice, restored antitumor T cell activity, and increased Ag cross-presentation within the tumor microenvironment. Furthermore, combination therapy consisting of rIL-33 and agonistic anti-CD40 Abs demonstrated synergistic antitumor activity. Specifically, MyD88, an essential component of the IL-33 signaling pathway, was required for the IL-33-mediated increase in mDC number and upregulation in expression of costimulatory molecules. Importantly, we identified that the IL-33 receptor ST2, MyD88, and STAT1 cooperate to induce costimulatory molecule expression on mDCs in response to rIL-33. Thus, our study revealed a novel IL-33-ST2-MyD88-STAT1 axis that restores mDC activation and maturation in established cancer and, thereby, the magnitude of antitumor immune responses, suggesting a potential use of rIL-33 as a new immunotherapy option to treat established cancer.
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Donye
authors.identifier: 0000-0002-4413-9376
authors.initials: D
authors.lastname: Dominguez
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Cong
authors.identifier: 0000-0001-5478-7361
authors.initials: C
authors.lastname: Ye
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Geng
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Siqi
authors.identifier: 0000-0002-9498-3823
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Lei
authors.identifier: 0000-0002-5951-1425
authors.initials: L
authors.lastname: Qin
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Alan
authors.initials: A
authors.lastname: Long
authors.affiliation: Cancer Therapy and Research Center, Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229.
authors.forename: Long
authors.identifier: 0000-0002-7935-4148
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Zhuoli
authors.identifier: 0000-0001-5243-4001
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; and.
authors.forename: Yi
authors.identifier: 0000-0001-9861-4681
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Kuzel
authors.affiliation: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; bin.zhang@northwestern.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000502:physiology; D000067596:Interleukin-33 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D009374:Neoplasms, Experimental / Q000276:immunology*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D019013:CD40 Antigens; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse