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 demo... More
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.
