Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors
Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors
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DOI：
10.1073/pnas.1113099109
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发表时间：
2012-02-07
影响因子：
11.1
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
--
作者：
Shime, Hiroaki;Matsumoto, Misako;Seya, Tsukasa
郁积性炎症通常会增加恶性肿瘤进展的风险，同时使髓样树突状细胞（mDC）成熟，用于细胞介导的免疫。据报道，PolyI：C是一种dsRNA类似物，可通过mDC中的Toll样受体3/Toll-IL-1受体结构域衔接分子1（TICAM-1）和黑素瘤分化相关蛋白5/IFN-β启动子刺激因子1（IPS-1）途径诱导炎症和强效抗肿瘤免疫应答，以驱动自然杀伤细胞和细胞毒性T淋巴细胞的活化。在这里，我们发现i. p.或s.c.向刘易斯肺癌肿瘤植入小鼠注射聚I：C通过将肿瘤支持巨噬细胞（Mfs）转化为肿瘤抑制物而导致肿瘤消退。浸润肿瘤的F4/80（+）/Gr 1（-）Mfs对polyI：C应答，迅速产生炎性细胞因子，此后加速M1极化。肿瘤和血清中的TNF-α在1小时内增加后polyI：C注射到荷瘤小鼠，随后肿瘤出血性坏死和生长抑制。这些肿瘤反应在TNF-α-/小鼠中消除。此外，从注射polyI：C的小鼠中提取的肿瘤中的F4/80（+）Mfs维持刘易斯肺癌细胞毒活性，并且该活性被抗TNF-α Ab部分消除。支持M1极化的基因随后在肿瘤浸润Mfs中上调。这些反应在TICAM-1（-/-）小鼠中完全消除，在髓样分化因子88（-/-）和IPS-1（-/-）小鼠中不受影响。因此，TICAM-1通路不仅对于成熟mDC在诱导肿瘤免疫中的交叉致敏和自然杀伤细胞活化是重要的，而且通过将肿瘤支持Mfs转化为具有杀肿瘤特性的Mfs而关键地参与肿瘤抑制。
Smoldering inflammation often increases the risk of progression for malignant tumors and simultaneously matures myeloid dendritic cells (mDCs) for cell-mediated immunity. PolyI:C, a dsRNA analog, is reported to induce inflammation and potent antitumor immune responses via the Toll-like receptor 3/Toll-IL-1 receptor domain-containing adaptor molecule 1 (TICAM-1) and melanoma differentiation-associated protein 5/IFN-beta promoter stimulator 1 (IPS-1) pathways in mDCs to drive activation of natural killer cells and cytotoxic T lymphocytes. Here, we found that i.p. or s.c. injection of polyI:C to Lewis lung carcinoma tumor-implant mice resulted in tumor regression by converting tumor-supporting macrophages (Mfs) to tumor suppressors. F4/80(+)/Gr1(-) Mfs infiltrating the tumor respond to polyI:C to rapidly produce inflammatory cytokines and thereafter accelerate M1 polarization. TNF-alpha was increased within 1 h in both tumor and serum upon polyI: C injection into tumor-bearing mice, followed by tumor hemorrhagic necrosis and growth suppression. These tumor responses were abolished in TNF-alpha-/mice. Furthermore, F4/80(+) Mfs in tumors extracted from polyI:C-injected mice sustained Lewis lung carcinoma cytotoxic activity, and this activity was partly abrogated by anti-TNF-alpha Ab. Genes for supporting M1 polarization were subsequently up-regulated in the tumor-infiltrating Mfs. These responses were completely abrogated in TICAM-1(-/-) mice, and unaffected in myeloid differentiation factor 88(-/-) and IPS-1(-/-) mice. Thus, the TICAM-1 pathway is not only important to mature mDCs for cross-priming and natural killer cell activation in the induction of tumor immunity, but also critically engaged in tumor suppression by converting tumor-supporting Mfs to those with tumoricidal properties.