The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells.
The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells.
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DOI：
10.1158/0008-5472.can-10-1921
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Ting JP
中科院分区：
文献类型：
--
作者：
van Deventer HW;Burgents JE;Wu QP;Woodford RM;Brickey WJ;Allen IC;McElvania-Tekippe E;Serody JS;Ting JP
炎性体是一种蛋白水解复合物，其产生活性形式的促炎细胞因子IL-1β和IL-18。炎性小体激活由响应微生物和非微生物刺激的NLR蛋白介导。在NLR中，NLRP 3能够感知最广泛的刺激并增强适应性免疫力。然而，其在抗肿瘤免疫中的作用尚不清楚。因此，我们评估了NLRP 3炎性体在免疫应答中的功能，使用树突状细胞接种针对免疫原性差的黑素瘤细胞系B16-F10。与对照动物相比，Nlrp 3 −/−小鼠的疫苗接种导致存活率相对提高4倍。免疫依赖于CD 8 + T细胞，并表现出免疫特异性和记忆性。Nlrp 3 −/−宿主中疫苗效力的增加并不反映树突状细胞的差异，而是反映髓源性抑制细胞（MDSC）的差异。尽管Nlrp 3在MDSC中表达，但Nlrp 3的缺乏并不改变其抑制T细胞的功能能力或其在外周淋巴组织中的存在。相反，Nlrp 3的缺乏导致宿主小鼠中发现的肿瘤相关MDSC数量减少5倍。连续转移实验也表明，Nlrp 3 −/− MDSC到达肿瘤部位的效率较低。用抗Gr-1抗体耗尽MDSC增加了荷瘤野生型小鼠的存活率，但Nlrp 3 −/−小鼠没有。我们的结论是，Nlrp 3是关键的MDSC在肿瘤中的积累和抑制抗肿瘤T细胞免疫后，树突状细胞接种。我们的研究结果确立了Nlrp 3在阻碍抗肿瘤免疫应答中的意想不到的作用，表明了通过限制Nlrp 3信号传导来改善对抗肿瘤疫苗的应答的新方法。
The inflammasome is a proteolysis complex that generates the active forms of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasome activtation is mediated by NLR proteins that respond to microbial and nonmicrobial stimuli. Among NLRs, NLRP3 senses the widest array of stimuli and enhances adaptive immunity. However, its role in antitumor immunity is unknown. Therefore, we evaluated the function of the NLRP3 inflammasome in the immune response using dendritic cell vaccination against the poorly immunogenic melanoma cell line B16-F10. Vaccination of Nlrp3−/− mice led to a relative 4-fold improvement in survival relative to control animals. Immunity depended upon CD8+ T cells and exhibited immune specificity and memory. Increased vaccine efficacy in Nlrp3−/− hosts did not reflect differences in dendritic cells but rather differences in myeloid-derived suppressor cells (MDSCs). Although Nlrp3 was expressed in MDSCs, the absence of Nlrp3 did not alter either their functional capacity to inhibit T cells or their presence in peripheral lymphoid tissues. Instead, the absence of Nlrp3 caused a 5-fold reduction in the number of tumor-associated MDSCs found in host mice. Adoptive transfer experiments also showed that Nlrp3−/− MDSCs were less efficient in reaching the tumor site. Depleting MDSCs with an anti-Gr-1 antibody increased the survival of tumor-bearing wild-type mice but not Nlrp3−/− mice. We concluded that Nlrp3 was critical for accumulation of MDSCs in tumors and for inhibition of antitumor T cell immunity after dendritic cell vaccination. Our findings establish an unexpected role for Nlrp3 in impeding antitumor immune responses, suggesting novel approaches to improve the response to antitumor vaccines by limiting Nlrp3 signaling.