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首页> 外文期刊>Journal of Translational Medicine >Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models
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Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models

机译：Toll样受体3配体多ICLC促进鼠中枢神经系统肿瘤模型中肿瘤抗原衍生肽表位的外周疫苗接种

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Background Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations. Methods C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes- mEphA2 (671–679), hgp100 (25–33) and mTRP-2 (180–188) for GL261, or ovalbumin (OVA: 257–264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC. Results The combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-γ by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity. Conclusion These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.
机译：背景Toll样受体（TLR）3配体是促炎细胞因子的天然诱导物，能够促进1型适应性免疫，并且TLR3在中枢神经系统（CNS）中大量表达。为了提高针对中枢神经系统肿瘤的疫苗策略的疗效，我们评估了施用TLR3配体，用聚赖氨酸和羧甲基纤维素稳定的多肌苷酸-多胞苷（poly-IC）（poly-ICLC）是否可以增强抗CNS肿瘤的有效性。基于肿瘤肽的疫苗接种。方法携带同型中枢神经系统GL261神经胶质瘤或M05黑色素瘤的C57BL / 6小鼠接受皮下（sc）疫苗接种，合成肽编码CTL表位-mEphA2（671–679），hgp100（25–33）和mTRP-2（180–188）GL261或M05的卵清蛋白（OVA：257–264）。小鼠也接受了聚-ICLC的肌内（i.m.）注射。结果基于皮下（s.c.）肽的疫苗接种和i.m.多ICLC施用促进了表达非常晚期激活抗原（VLA）-4的抗原（Ag）特异性的Type-1 CTL的系统诱导，这基于单克隆抗体（mAb）的实验赋予疫苗诱导的CTL有效的CNS肿瘤归巢介导的VLA-4封锁。此外，联合治疗允许中枢神经系统肿瘤浸润性CTL表达IFN-γ，并在没有可检测的自身免疫的情况下提高了荷瘤小鼠的存活率。结论这些数据表明，先前在临床试验中评估过的聚-ICLC可与肿瘤银特异性疫苗策略有效结合，从而提供更大的治疗效果指标。

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