Circulating nano-particulate TLR9 agonist scouts out tumor microenvironment to release immunogenic dead tumor cells.
Circulating nano-particulate TLR9 agonist scouts out tumor microenvironment to release immunogenic dead tumor cells.
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DOI：
10.18632/oncotarget.10379
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发表时间：
2016-08-02
期刊：
影响因子：
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通讯作者：
Ishii KJ
中科院分区：
文献类型：
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作者：
Kitahata Y;Kanuma T;Hayashi M;Kobayashi N;Ozasa K;Kusakabe T;Temizoz B;Kuroda E;Yamaue H;Coban C;Yamamoto T;Kobiyama K;Aoshi T;Ishii KJ
最近的证据表明，来源于蘑菇裂褶多糖（SPG）的β-葡聚糖与人源化TLR 9激动性CpG DNA K3（K3-SPG）复合，是一种有前途的疫苗佐剂，其诱导对共同施用的抗原的稳健的CD 8 T细胞应答。然而，还没有研究单独的K3-SPG是否可以作为抗癌免疫抑制剂。在这里，我们证明，静脉注射K3-SPG，而不是单独的CpG，是积累在肿瘤微环境和触发免疫原性细胞死亡（ICD）的肿瘤细胞的局部诱导的I型干扰素（IFN）以及IL-12。由此产生的先天免疫激活以及随后的肿瘤特异性CD 8 T细胞应答有助于肿瘤生长抑制。K3-SPG单药治疗的这种抗肿瘤作用也通过使用各种肿瘤模型包括胰腺癌腹膜播散模型来证实。总之，静脉内注射的纳米颗粒TLR 9激动剂可以侦察肿瘤微环境以引起局部先天免疫激活并将死亡的肿瘤细胞释放到循环中，这可以诱导更广泛和保护性的肿瘤抗原特异性CD 8 T细胞。
Recent evidence suggest that a β-glucan derived from mushroom Schizophyllan(SPG) complexed with a humanized TLR9 agonistic CpG DNA, K3 (K3-SPG) is a promising vaccine adjuvant that induces robust CD8 T cell responses to co-administered antigen. However, it has not been investigated whether K3-SPG alone can act as an anti-cancer immunotherapeutic agent or not. Here, we demonstrate that intravenous injection of K3-SPG, but not CpG alone, is accumulated in the tumor microenvironment and triggered immunogenic cell death (ICD) of tumor cells by local induction of type-I interferon (IFN) as well as IL-12. Resultant innate immune activation as well as subsequent tumor-specific CD8 T cell responses were contributed the tumor growth suppression. This anti-tumor effect of K3-SPG monotherapy was also confirmed by using various tumor models including pancreatic cancer peritoneal dissemination model. Taken together, nano-particulate TLR9 agonist injected intravenously can scout out tumor microenvironment to provoke local innate immune activation and release dead tumor cells into circulation that may induce broader and protective tumor antigen-specific CD8 T cells.