Scheel Birgit, Aulwurm Steffen, Probst Jochen, Stitz Lothar, Hoerr Ingmar, Rammensee Hans-Georg, Weller Michael, Pascolo Steve
Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
Eur J Immunol. 2006 Oct;36(10):2807-16. doi: 10.1002/eji.200635910.
Stabilized synthetic RNA oligonucleotides (ORN) and protected messenger RNA (mRNA) were recently discovered to possess an immunostimulatory capacity through their recognition by TLR 7 and 8. We wanted to find out whether this danger signal is capable of triggering anti-tumor immunity when injected locally into an established tumor. Using the mouse glioma tumor cell line SMA-560 in syngenic VM/Dk mice, we were able to show that intra-tumor injections of protamine-stabilized mRNA do indeed induce tumor regression and long-term anti-tumor immunity. Residual RNA-injected tumors show CD8 infiltration. Distant injections of protamine-protected mRNA and intra-tumor injection of naked mRNA also result in anti-tumor immunity. Although they are strong danger signals, RNA are labile molecules with a short half-life: they do not trigger side effects such as long-term, uncontrolled immunostimulation evidenced by splenomegaly in CpG DNA-treated mice. In conclusion, RNA molecules are potent and safe danger signals that are relevant for active immunotherapy strategies aimed at the eradication of solid tumors.
最近发现，稳定化的合成RNA寡核苷酸（ORN）和经保护的信使RNA（mRNA）可通过Toll样受体7（TLR 7）和Toll样受体8（TLR 8）的识别而具有免疫刺激能力。我们想弄清楚，当将这种危险信号局部注射到已形成的肿瘤中时，是否能够触发抗肿瘤免疫。利用同基因VM/Dk小鼠体内的小鼠胶质瘤肿瘤细胞系SMA-560，我们能够证明，肿瘤内注射鱼精蛋白稳定化的mRNA确实能诱导肿瘤消退和长期抗肿瘤免疫。注射RNA后残留的肿瘤出现CD8浸润。远距离注射鱼精蛋白保护的mRNA以及肿瘤内注射裸露的mRNA也会产生抗肿瘤免疫。尽管RNA是强大的危险信号，但它们是半衰期短的不稳定分子：它们不会引发诸如长期、不受控制的免疫刺激等副作用，而在经CpG DNA处理的小鼠中，脾肿大就证明了存在这种免疫刺激。总之，RNA分子是强大且安全的危险信号，与旨在根除实体瘤的主动免疫治疗策略相关。
