Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy
Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy
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DOI：
10.1016/j.biomaterials.2018.02.034
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发表时间：
2018-05-01
期刊：
影响因子：
14
通讯作者：
Panyam, Jayanth
中科院分区：
文献类型：
--
作者：
Kim, Hyunjoon;Niu, Lin;Panyam, Jayanth
细胞毒性T淋巴细胞（CTL）由于其直接杀伤肿瘤细胞并分泌肿瘤抑制性细胞因子的能力而在癌症免疫治疗中起主要作用。抗癌疫苗旨在激发肿瘤特异性CTL应答，这需要活化抗原呈递细胞（APC），包括树突状细胞（DC）和巨噬细胞。因此，能够激活APC的有效免疫刺激佐剂是抗癌疫苗的重要组成部分。在这项研究中，我们介绍了新的TLR 7/8双特异性激动剂，显着增强细胞因子分泌相比，TLR 7单选择性化合物。与可溶性激动剂相比，将这些TLR 7/8激动剂封装在聚（丙交酯-共-乙交酯）（PLGA）纳米颗粒中增加了DC通过MHC I的共刺激分子表达和抗原呈递。当皮下给药时，这些纳米颗粒迁移到引流淋巴结并触发DC活化和扩增。这导致抗原特异性CD 8 T细胞的扩增和增强的CTL应答，这导致在黑色素瘤、膀胱和肾细胞癌肿瘤模型中的显著预防和治疗功效。重要的是，我们的研究证明了纳米颗粒疫苗显著降低了全身转移。我们的研究结果表明，新型TLR 7/8激动剂包封的纳米颗粒是癌症免疫治疗的有效免疫刺激佐剂。(C)2018由Elsevier Ltd.出版
Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds. Encapsulation of these TLR 7/8 agonists in poly(lactide-co-glycolide) (PLGA) nanoparticles increased the co-stimulatory molecule expression and antigen presentation via MHC I by DCs compared to the soluble agonist. When administered subcutaneously, these nanoparticles migrated to draining lymph node and triggered DC activation and expansion. This lead to expansion of antigen-specific CD8 T cells and enhanced CTL response, which resulted in significant prophylactic and therapeutic efficacy in melanoma, bladder and renal cell carcinoma tumor models. Importantly, our studies demonstrate significant reductions in systemic metastasis with the nanoparticle vaccine. Our results suggest novel TLR 7/8 agonist-encapsulated nanoparticles are potent immunostimulatory adjuvants for cancer immunotherapy. (C) 2018 Published by Elsevier Ltd.