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.

细胞毒性T淋巴细胞（CTL）在癌症免疫治疗中起主要作用，因为它们具有直接杀死肿瘤细胞和分泌肿瘤抑制性细胞因子的能力。抗癌疫苗旨在引起肿瘤特异性CTL反应，这需要激活抗原呈递细胞（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，我们介绍了新颖的TLR 7/8双特异性激动剂，与TLR7单选择化合物相比，它们显着增强了细胞因子的分泌。在这些聚TLR 7/8激动剂的封装（丙交酯-共与可溶性激动剂相比，β-乙交酯（PLGA）纳米颗粒通过DC通过MHC I增加了共刺激分子的表达和抗原呈递。当皮下给药时，这些纳米颗粒迁移至引流淋巴结并触发DC活化和扩增。这导致抗原特异性CD8 T细胞扩增和增强的CTL反应，从而在黑素瘤，膀胱和肾细胞癌肿瘤模型中产生了显着的预防和治疗功效。重要的是，我们的研究表明纳米颗粒疫苗可显着减少全身转移。我们的结果表明，新型TLR 7/8激动剂包裹的纳米颗粒是用于癌症免疫疗法的有效免疫刺激佐剂。