Original The IL-33/ST2 pathway suppresses murine colon cancer growth and metastasis by upregulating CD40 L signaling
Original The IL-33/ST2 pathway suppresses murine colon cancer growth and metastasis by upregulating CD40 L signaling
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DOI：
10.1016/j.biopha.2020.110232
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发表时间：
2020-07-01
影响因子：
7.5
通讯作者：
Han, Wei
中科院分区：
文献类型：
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作者：
Luo, Ping;Deng, Shaorong;Han, Wei
白细胞介素（IL）-33是IL-1家族的成员，参与辅助性T1（Th 1）和Th 2型免疫应答，但其对肿瘤生长的模糊作用和相关的免疫机制仍不清楚。在这里，我们报告，重组小鼠IL-33（mIL-33）显着抑制结肠癌的生长和转移到肺和肝的小鼠CT 26或MC 38肿瘤细胞移植模型。这种作用可能与CD 4 +T细胞和CD 40 L信号转导有关，因为体内清除CD 4 +T细胞或阻断CD 40 L信号转导可部分消除IL-33的抗肿瘤作用。此外，IL-33处理上调肿瘤浸润淋巴细胞上的CD 40 L表达，并通过CD 40 L信号通路促进CD 4 +T、CD 8 +T和自然杀伤细胞的活化。IL-33可诱导CD 4 +T细胞表达ST 2，但对CD 8 +T细胞和NK细胞无明显影响，提示IL-33通过正反馈环作用于CD 4 +T细胞。我们的研究结果揭示了IL-33介导的抗肿瘤作用和Th 1作用机制，也表明IL-33可以作为激活剂，以提高单一或联合治疗的抗癌免疫反应。
Interleukin (IL)-33 is a member of the IL-1 family, participating in both helper T1 (Th1)- and Th2-type immune responses, but its ambiguous effects on tumor growth and related immune mechanisms remain unclear. Here, we report that recombinant mouse IL-33 (mIL-33) significantly inhibited colon cancer growth and metastasis to lung and liver in a murine CT26 or MC38 tumor-cell engraftment model. This effect could be associated with CD4+T cells and CD40 L signaling, as depletion of CD4+T cells or blocking CD40 L signalingin vivopartly abolished the antitumor function of IL-33. In addition, IL-33 treatment upregulated CD40 L expression on tumor-infiltrating lymphocytes, and promoted the activation of CD4+T, CD8+T and natural killer cellsviaCD40 L signaling. Furthermore, IL-33 was sufficient to induce the ST2 expression on CD4+T cells, but not on CD8+T and natural killer cells, indicating that IL-33 acted on CD4+T cellsviaa positive-feedback loop. Our findings shed new light on the IL-33-mediated antitumor effects and mechanisms of Th1 action, and also suggest that IL-33 may serve as an activator to boost anticancer immune responses in singular or combinatory therapies.