Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells
Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells
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DOI：
10.1172/jci61034
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发表时间：
2012-02-01
影响因子：
15.9
通讯作者：
Sibilia, Maria
中科院分区：
文献类型：
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作者：
Drobits, Barbara;Holcmann, Martin;Sibilia, Maria
咪喹莫特是一种具有抗肿瘤特性的合成化合物；5%的乳霜配方成功地用于治疗皮肤肿瘤。咪喹莫特的抗肿瘤作用是多因素的，尽管其通过触发TLR7/8调节免疫反应的能力被认为是关键。其中被认为参与的免疫细胞包括浆细胞样dc （pDCs）。然而，pDCs在体内对肿瘤杀伤的直接贡献及其在咪喹莫特治疗部位的募集机制尚未得到证实。使用小鼠黑色素瘤模型，我们现在已经证明，pDCs可以直接清除肿瘤，而不需要适应性免疫系统。局部咪喹莫特治疗导致肥大细胞中tlr7依赖性和ifn - α / β受体1依赖性（ifnri依赖性）趋化因子CCL2的表达上调。这对于诱导皮肤炎症和向皮肤募集pDCs至关重要。招募的pDCs是CD8 α(+)，并以TLR7/MyD88-和ifnari依赖的方式诱导肿瘤消退。荷瘤小鼠TLR7和IFNAR1的缺失或pDCs或CD8 α(+)细胞的缺失完全消除了咪喹莫特的作用。TLR7是吡虫胺刺激的pDCs产生ifn - α / β所必需的，这导致pDCs通过IFNAR1信号通路分泌TRAIL和颗粒酶B。阻断这些细胞溶解分子会破坏pdc介导的肿瘤杀伤。我们的研究结果表明，咪喹莫特治疗可导致依赖ccl2的pDCs募集，并将其转化为能够直接消除肿瘤细胞的杀伤dc亚群。
Imiquimod is a synthetic compound with antitumor properties; a 5% cream formulation is successfully used to treat skin tumors. The antitumor effect of imiquimod is multifactorial, although its ability to modulate immune responses by triggering TLR7/8 is thought to be key. Among the immune cells suggested to be involved are plasmacytoid DCs (pDCs). However, a direct contribution of pDCs' to tumor killing in vivo and the mechanism of their recruitment to imiquimod-treated sites have never been demonstrated. Using a mouse model of melanoma, we have now demonstrated that pDCs can directly clear tumors without the need for the adaptive immune system. Topical imiquimod treatment led to TLR7-dependent and IFN-alpha/beta receptor 1-dependent (IFNARI-dependent) upregulation of expression of the chemokine CCL2 in mast cells. This was essential to induce skin inflammation and for the recruitment of pDCs to the skin. The recruited pDCs were CD8 alpha(+) and induced tumor regression in a TLR7/MyD88- and IFNARI-dependent manner. Lack of TLR7 and IFNAR1 or depletion of pDCs or CD8 alpha(+) cells from tumor-bearing mice completely abolished the effect of imiquimod. TLR7 was essential for imiquimod-stimulated pDCs to produce IFN-alpha/beta, which led to TRAIL and granzyme B secretion by pDCs via IFNAR1 signaling. Blocking these cytolytic molecules impaired pDC-mediated tumor killing. Our results demonstrate that imiquimod treatment leads to CCL2-dependent recruitment of pDCs and their transformation into a subset of killer DCs able to directly eliminate tumor cells.