Exogenous IL-33 Restores Dendritic Cell Activation and Maturation in Established Cancer.
Exogenous IL-33 Restores Dendritic Cell Activation and Maturation in Established Cancer.
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外源IL-33恢复了既定癌症的树突状细胞的活化和成熟。
DOI：
10.4049/jimmunol.1501399
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发表时间：
2017-02-01
期刊：
影响因子：
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通讯作者：
Zhang B
中科院分区：
文献类型：
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作者：
Dominguez D;Ye C;Geng Z;Chen S;Fan J;Qin L;Long A;Wang L;Zhang Z;Zhang Y;Fang D;Kuzel TM;Zhang B
IL-33在肿瘤生长和肿瘤免疫中的作用仍不明确。我们在这里表明，外源性IL-33可以通过CD8+ T细胞依赖机制诱导强大的抗肿瘤作用。在移植和新生黑色素瘤发生模型中，单系统给药重组IL-33 （IL-33）足以抑制已建立肿瘤的生长。值得注意的是，除了直接作用于CD8+ T细胞扩增和IFN-γ产生外，rIL-33治疗还激活了荷瘤小鼠的骨髓树突状细胞（mDCs），恢复了抗肿瘤T细胞活性，并增加了肿瘤微环境中的抗原交叉递呈。此外，il -33和激动性抗cd40抗体联合治疗显示出协同抗肿瘤活性。具体来说，MyD88是IL-33信号通路的重要组成部分，是IL-33介导的mDC数量增加和共刺激分子表达上调所必需的。重要的是，我们发现IL-33受体ST2、MyD88和STAT1协同诱导细胞对IL-33的共刺激分子表达。因此，我们的研究揭示了一种新的IL-33-ST2-MyD88-STAT1轴，它可以恢复癌症中mDC的激活和成熟，从而提高抗肿瘤免疫反应的强度，这表明il -33有可能成为治疗癌症的一种新的免疫治疗选择。
The role of IL-33 particularly in tumor growth and tumor immunity remains ill defined. We show here that exogenous IL-33 can induce robust antitumor effect through a CD8+ T cell-dependent mechanism. Systemic administration of recombinant IL-33 (rIL-33) alone was sufficient to inhibit growth of established tumors in both 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 antigen cross-presentation within the tumor microenvironment. Furthermore, combination therapy with rIL-33 and agonistic anti-CD40 antibodies 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 of costimulatory molecule expression. 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. Our study has thus revealed a novel IL-33-ST2-MyD88-STAT1 axis that restores mDC activation and maturation in established cancer, and thereby the magnitude of anti-tumor immune responses, suggesting a potential use of rIL-33 as a new immunotherapy option to treat established cancer.