Molecular Immunology and Pharmacology Laboratory, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PLoS One. 2011;6(9):e24705. doi: 10.1371/journal.pone.0024705. Epub 2011 Sep 13.
Immunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown.
Using a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFNγ/STAT1 activation and attenuated tumor metastasis. IFNγ neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFNγ/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis.
Our studies suggest that activation of IFNγ/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis.
免疫疗法常被推荐作为辅助治疗，以降低癌症复发或转移的几率。有趣的是，尽管确切的机制仍不清楚，但对于成功的转移性免疫治疗来说，时机非常重要。
我们使用静脉注射 B16-F10 细胞诱导的黑色素瘤转移小鼠模型，研究了 TLR4 和 TLR9 激动剂复合物对转移的不同疗效的预防或治疗作用的机制。我们发现，TLR4 和 TLR9 的激活可以预防，但不能逆转转移，因为这种组合的效力既不足以克服肿瘤细胞诱导的免疫耐受，也不能诱导肿瘤细胞中有效的自噬。该复合物的预防性应用促进了抗转移免疫，通过 IFNγ/STAT1 激活和减弱肿瘤转移导致黑色素瘤细胞的自噬相关死亡。IFNγ 中和通过抑制 STAT1 激活和减弱小鼠中的自噬，逆转了复合物诱导的预防性益处。然而，复合物的治疗应用并不能抑制转移，因为复合物不能逆转肿瘤细胞诱导的 STAT3 激活，也不能激活 IFNγ/STAT1 信号和自噬。使用 JAK/STAT 拮抗剂 AG490 抑制 STAT3 激活恢复了 TLR4/9 激动剂复合物的抗转移作用。在用雷帕霉素（单独或与 TLR4/9 激动剂复合物一起）在肿瘤接种后激活自噬，可以抑制转移。
我们的研究表明，IFNγ/STAT1 信号的激活和自噬的诱导对于有效的抗转移性免疫治疗至关重要，并且自噬激活剂可能克服免疫治疗转移性的时间障碍。
