An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma
An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma
复制标题
ISCOM 疫苗与 TLR9 激动剂相结合，打破了胰腺癌原位模型中调节性 T 细胞介导的免疫逃避
DOI：
10.1002/ijc.25399
复制
发表时间：
2011-02-15
影响因子：
6.4
通讯作者：
Schnurr, Max
中科院分区：
文献类型：
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作者：
Jacobs, Collin;Duewell, Peter;Schnurr, Max
基于免疫刺激复合物（ISCOM）的疫苗诱导针对肿瘤抗原（Ag）的T细胞应答。然而，胰腺癌患者的免疫反应受损。我们研究了ISCOM疫苗在小鼠胰腺癌模型中的功效。在C57 BL/6小鼠胰腺中皮下或原位诱导表达OVA的Panc 02细胞作为模型Ag。治疗由单独使用或与TLR 9激动剂CpG组合使用的含有OVA的ISCOM疫苗组成。ISCOM疫苗有效地诱导能够杀伤肿瘤细胞的Ag特异性CTL。然而，在已建立肿瘤的小鼠中，疫苗的CTL诱导是无效的，并且不影响肿瘤生长。缺乏疗效与Treg数量增加相关。用抗CD 25 mAb耗尽Treg恢复了CTL诱导并延长了存活。在ISCOM疫苗中加入低剂量CpG可减少Treg数量，增强CTL应答，并以CD 8（+）T细胞依赖性方式诱导胰腺肿瘤消退。从原发性肿瘤治愈的小鼠产生了针对野生型Panc 02肿瘤的记忆T细胞应答，指示表位扩散。ISCOM疫苗与TLR激动剂联合使用是打破肿瘤免疫逃避的一种有前途的策略，值得进一步评估其治疗胰腺癌的效果。
Vaccines based on immune stimulatory complexes (ISCOM) induce T-cell responses against tumor antigen (Ag). However, immune responses are impaired in pancreatic cancer patients. We investigated the efficacy of an ISCOM vaccine in a murine pancreatic carcinoma model. Panc02 cells expressing OVA as a model Ag were induced subcutaneously or orthotopically in the pancreas of C57BL/6 mice. Treatment consisted of an OVA containing ISCOM vaccine, either used alone or in combination with the TLR9 agonist CpG. The ISCOM vaccine effectively induced Ag-specific CTL capable of killing tumor cells. However, in mice with established tumors CTL induction by the vaccine was inefficient and did not affect tumor growth. Lack of efficacy correlated with increased numbers of Treg. Depletion of Treg with anti-CD25 mAb restored CTL induction and prolonged survival. Adding low-dose CpG to the ISCOM vaccine reduced Treg numbers, enhanced CTL responses and induced regression of pancreatic tumors in a CD8(+) T cell dependent manner. Mice cured from the primary tumor mounted a memory T-cell response against wildtype Panc02 tumors, indicative of epitope spreading. Combining ISCOM vaccines with TLR agonists is a promising strategy for breaking tumor immune evasion and deserves further evaluation for the treatment of pancreatic carcinoma.