Journal
JOURNAL OF IMMUNOLOGY
Volume 198, Issue 3, Pages 1365-1375Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1501399
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Funding
- National Institutes of Health [CA149669]
- Northwestern Memorial Foundation-Friends of Prentice Grants Initiative
- Specialized Programs of Research Elements Pilot Award [P50 CA090386]
- Cancer Center Support Grant [NCI CA060553]
- Northwestern University Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Facility
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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-gamma 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.
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