Exogenous IL-33 restores dendritic cell activation and maturation in established cancer

Donye Dominguez, Cong Ye, Zhe Geng, Siqi Chen, Jie Fan, Lei Qin, Alan Long, Long Wang, Zhuoli Zhang, Yi Zhang, Deyu Fang, Timothy M. Kuzel, Bin Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1365-1375
Number of pages11
JournalJournal of Immunology
Volume198
Issue number3
DOIs
StatePublished - Feb 1 2017

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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