A Critical Role for Mast Cells and Mast Cell-Derived IL-6 in TLR2-Mediated Inhibition of Tumor Growth
A Critical Role for Mast Cells and Mast Cell-Derived IL-6 in TLR2-Mediated Inhibition of Tumor Growth
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DOI：
10.4049/jimmunol.1001137
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发表时间：
2010-12-01
影响因子：
4.4
通讯作者：
Marshall, Jean S.
中科院分区：
文献类型：
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作者：
Oldford, Sharon A.;Haidl, Ian D.;Marshall, Jean S.
几种TLR激动剂在肿瘤免疫治疗中是有效的，但它们的早期先天作用机制，特别是TLR2激动剂的作用机制尚不清楚。肥大细胞在实体瘤周围大量存在，它们通常具有致瘤性并促进肿瘤血管生成。然而，肥大细胞的抗肿瘤作用也有文献记载。肥大细胞的作用可能取决于它们在不同肿瘤中的激活状态和介质释放。在野生型C57BL/6和肥大细胞缺陷试剂盒（W-sh/W-sh）小鼠的原位黑色素瘤模型和C57BL/6小鼠的互补基质肿瘤模型中，肥大细胞被证明对TLR2激动剂(Pam（3)CSK(4)）诱导的肿瘤抑制至关重要。肥大细胞上TLR2的激活逆转了它们有充分证据的致瘤作用。在Kit（W-sh/W-sh）小鼠瘤周给予Pam(3)CSK(4)后，通过局部重建野生型肥大细胞而非tlr2缺陷肥大细胞，恢复了肿瘤生长抑制。肥大细胞在Pam(3)CSK(4)激活后分泌多种介质，体内肥大细胞重构研究也表明，肿瘤生长抑制需要肥大细胞来源的IL-6，而不是TNF。肥大细胞介导的抗癌特性是多方面的。在体外观察到直接的抗肿瘤作用，在体内观察到减少血管生成和NK细胞和T细胞的募集。tlr2激活的肥大细胞在体内也能抑制肺癌细胞的生长。与其他免疫细胞不同，肥大细胞具有相对的抗辐射性，这使它们成为联合治疗方式的有吸引力的候选者。这项研究对免疫治疗策略的设计具有重要意义，并揭示了TLR2激动剂在体内的一种新的作用机制。中华免疫学杂志，2010,18(5):7067-7076。
Several TLR agonists are effective in tumor immunotherapy, but their early innate mechanisms of action, particularly those of TLR2 agonists, are unclear. Mast cells are abundant surrounding solid tumors where they are often protumorigenic and enhance tumor angiogenesis. However, antitumor roles for mast cells have also been documented. The impact of mast cells may be dependent on their activation status and mediator release in different tumors. Using an orthotopic melanoma model in wild-type C57BL/6 and mast cell-deficient Kit(W-sh/W-sh) mice and a complementary Matrigel-tumor model in C57BL/6 mice, mast cells were shown to be crucial for TLR2 agonist (Pam(3)CSK(4))-induced tumor inhibition. Activation of TLR2 on mast cells reversed their well-documented protumorigenic role. Tumor growth inhibition after peritumoral administration of Pam(3)CSK(4) was restored in Kit(W-sh/W-sh) mice by local reconstitution with wild-type, but not TLR2-deficient, mast cells. Mast cells secrete multiple mediators after Pam(3)CSK(4) activation, and in vivo mast cell reconstitution studies also revealed that tumor growth inhibition required mast cell-derived IL-6, but not TNF. Mast cell-mediated anticancer properties were multifaceted. Direct antitumor effects in vitro and decreased angiogenesis and recruitment of NK and T cells in vivo were observed. TLR2-activated mast cells also inhibited the growth of lung cancer cells in vivo. Unlike other immune cells, mast cells are relatively radioresistant making them attractive candidates for combined treatment modalities. This study has important implications for the design of immunotherapeutic strategies and reveals, to our knowledge, a novel mechanism of action for TLR2 agonists in vivo. The Journal of Immunology, 2010, 185: 7067-7076.