NK1.1+ cells mediate the antitumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model
NK1.1+ cells mediate the antitumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model
复制标题
DOI：
10.1007/s00262-008-0581-7
复制
发表时间：
2009-04-01
影响因子：
5.8
通讯作者：
Gullikson, Gary W.
中科院分区：
文献类型：
--
作者：
Dumitru, Calin D.;Antonysamy, Mary A.;Gullikson, Gary W.
Toll样受体（TLR）激动剂的天然免疫刺激是黑色素瘤免疫治疗的建议模式。在此，TLR 7/8激动剂3 M-011被有效地用作针对播散性小鼠B16-F10黑色素瘤的单一全身性药剂。抗肿瘤作用机制的研究表明，该激动剂对体外试验的肿瘤细胞没有直接的细胞毒作用。此外，3 M-011在scid/B6小鼠和scid/NOD小鼠中保留了其有效性，消除了对T和B细胞的需求，但在米色（bg/bg）和NK 1.1免疫缺陷小鼠中失去了其活性，表明自然杀伤（NK）细胞在抗肿瘤反应中的关键作用。通过TLR 7/8激动剂在体内增强NK细胞毒性;这种活化是持久的，如通过活化标志物CD 69的持续表达所确定的。此外，在人体体外研究中，3 M-011可增强NK细胞毒性。TLR 7/8介导的NK依赖性抗肿瘤活性在IFN-α/β受体缺陷以及穿孔素缺陷小鼠中得以保留，而IFN-γ的消耗显著降低了3 M-011延迟肿瘤生长的能力。因此，NK细胞群体的IFN-γ依赖性功能似乎对于用TLR 7/8激动剂进行的癌症免疫治疗是必不可少的。
Innate immune stimulation with Toll-like receptor (TLR) agonists is a proposed modality for immunotherapy of melanoma. Here, a TLR7/8 agonist, 3M-011, was used effectively as a single systemic agent against disseminated mouse B16-F10 melanoma. The investigation of the mechanism of antitumor action revealed that the agonist had no direct cytotoxic effects on tumor cells tested in vitro. In addition, 3M-011 retained its effectiveness in scid/B6 mice and scid/NOD mice, eliminating the requirement for T and B cells, but lost its activity in beige (bg/bg) and NK1.1-immunodepleted mice, suggesting a critical role for natural killer (NK) cells in the antitumor response. NK cytotoxicity was enhanced in vivo by the TLR7/8 agonist; this activation was long lasting, as determined by sustained expression of the activation marker CD69. Also, in human in vitro studies, 3M-011 potentiated NK cytotoxicity. TLR7/8-mediated NK-dependent antitumor activity was retained in IFN-alpha/beta receptor-deficient as well as perforin-deficient mice, while depletion of IFN-gamma significantly decreased the ability of 3M-011 to delay tumor growth. Thus, IFN-gamma-dependent functions of NK cell populations appear essential for cancer immunotherapy with TLR7/8 agonists.