IL-33 Induces Sema4A Expression in Dendritic Cells and Exerts Antitumor Immunity
IL-33 Induces Sema4A Expression in Dendritic Cells and Exerts Antitumor Immunity
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DOI：
10.4049/jimmunol.2100076
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发表时间：
2021-09-01
影响因子：
4.4
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
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作者：
Suga, Yasuhiko;Nagatomo, Izumi;Kumanogoh, Atsushi
癌症免疫治疗作为一种新的标准治疗策略已经显示出巨大的前景。然而，缓解率和生存获益仍不令人满意，因为目前大多数方法，如使用免疫检查点抑制剂，依赖于自发的抗肿瘤免疫应答。提高免疫治疗效果的一种可能性是主动使用佐剂或特异性细胞因子促进抗肿瘤免疫。IL-33一直是这种细胞因子疗法的候选者，但IL-33如何以及在何种情况下发挥抗肿瘤免疫作用仍不清楚。在这项研究中，我们使用同基因小鼠模型证明了IL-33的强效抗肿瘤作用，包括显著抑制肿瘤生长和上调肿瘤浸润性CD 8（+）T细胞产生的IFN-γ。值得注意的是，IL-33诱导树突状细胞表达脑信号蛋白4A（Sema 4A），并且Sema 4A的缺乏消除了IL-33的抗肿瘤活性，表明Sema 4A是IL-33在小鼠中的抗肿瘤作用内在地需要的。总的来说，这些结果不仅将IL-33和Sema 4A作为潜在的治疗靶点，而且还揭示了Sema 4A作为树突状细胞活化状态的生物标志物的潜在用途，这在癌症研究的各个领域，包括疫苗开发中具有重要价值。
Cancer immunotherapy has shown great promise as a new standard therapeutic strategy against cancer. However, the response rate and survival benefit remain unsatisfactory because most current approaches, such as the use of immune checkpoint inhibitors, depend on spontaneous antitumor immune responses. One possibility for improving the efficacy of immunotherapy is to promote antitumor immunity using adjuvants or specific cytokines actively. IL-33 has been a candidate for such cytokine therapies, but it remains unclear how and in which situations IL-33 exerts antitumor immune effects. In this study, we demonstrate the potent antitumor effects of IL-33 using syngeneic mouse models, which included marked inhibition of tumor growth and upregulation of IFN-gamma production by tumor infiltrating CD8(+) T cells. Of note, IL-33 induced dendritic cells to express semaphorin 4A (Sema4A), and the absence of Sema4A abolished the antitumor activity of IL-33, indicating that Sema4A is intrinsically required for the antitumor effects of IL-33 in mice. Collectively, these results not only present IL-33 and Sema4A as potential therapeutic targets but also shed light on the potential use of Sema4A as a biomarker for dendritic cell activation status, which has great value in various fields of cancer research, including vaccine development.