Lymph Node Delivery Strategy Enables the Activation of Cytotoxic T Lymphocytes and Natural Killer Cells to Augment Cancer Immunotherapy
Lymph Node Delivery Strategy Enables the Activation of Cytotoxic T Lymphocytes and Natural Killer Cells to Augment Cancer Immunotherapy
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淋巴结递送策略能够激活细胞毒性 T 淋巴细胞和自然杀伤细胞，增强癌症免疫治疗
DOI：
10.1021/acsami.1c03709
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发表时间：
2021-05-06
影响因子：
9.5
通讯作者：
Zhang, Na
中科院分区：
文献类型：
--
作者：
Jiang, Dandan;Gao, Tong;Zhang, Na
淋巴结是免疫激活和监视的主要场所。将免疫调节剂有效递送至淋巴结以触发抗肿瘤免疫对于癌症治疗至关重要。在这里，我们提出了一种淋巴结递送策略，通过同时激活细胞毒性 T 淋巴细胞 (CTL) 和自然杀伤 (NK) 细胞来调节免疫反应。以聚(L-组氨酸)-聚(乙二醇)(PLH-PEG)为骨架制备了新型pH/氧化还原双敏感胶束，由于其合适的粒径，可以有效地将免疫调节剂递送至淋巴结。皮下注射后48 h，淋巴结积聚效率较对照组增加8.12倍。随后，Trp2/CpG共载pH/氧化还原双敏感胶束（Trp2/CpG-NPs）作用于抗原呈递细胞，通过树突状细胞抗原交叉呈递和巨噬细胞复极化充分促进CTL活化。开发了负载 IL-15 的 pH/氧化还原双敏感胶束 (IL-15-NP)，通过与 IL-15 受体相互作用来激活 NK 细胞的杀伤作用。在荷瘤小鼠模型中，这种淋巴结递送策略显示出显着的抗肿瘤效率，抑瘤率达到93.76%。同时，肿瘤组织中CTL和NK细胞的浸润增加，巨噬细胞从M2型复极化为M1型，免疫抑制微环境得到缓解。总的来说，这项研究强调了淋巴结递送策略在癌症免疫治疗中的潜力。
Lymph nodes are the main sites for immune activation and surveillance. Effective delivery of immunomodulators into lymph nodes to trigger antitumor immunity is essential for cancer treatment. Here, we propose a lymph node delivery strategy to modulate the immune response by activating cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells simultaneously. Novel pH/redox dual-sensitive micelles were prepared using poly(L-histidine)-poly(ethylene glycol) (PLH-PEG) as a skeleton, which can effectively deliver immunomodulators to the lymph nodes due to their suitable particle size. At 48 h after subcutaneous injection, the accumulation efficiency in lymph nodes increased 8.12-fold compared with the control group. Subsequently, Trp2/CpG-coloaded pH/redox dual-sensitive micelles (Trp2/CpG-NPs) acted on antigen-presenting cells, fully promoting CTL activation through dendritic cell antigen cross-presentation and macrophage repolarization. IL-15-loaded pH/redox dual-sensitive micelles (IL-15-NPs) were developed to activate the killing effect of NK cells by interacting with IL-15 receptors. In the tumor-bearing mice model, this lymph node delivery strategy showed significant antitumor efficiency and the tumor inhibition rate reached 93.76%. Meanwhile, the infiltration of CTLs and NK cells in tumor tissues increased, and the immunosuppressive microenvironment was relieved by the repolarization of macrophages from M2-type to M1-type. Overall, this study highlighted the potential of the lymph node delivery strategy for cancer immunotherapy.