Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses
Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses
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DOI：
10.1002/adma.201803397
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发表时间：
2018-11-01
影响因子：
29.4
通讯作者：
De Geest, Bruno G.
中科院分区：
文献类型：
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作者：
Nuhn, Lutz;De Koker, Stefaan;De Geest, Bruno G.
将肿瘤微环境从免疫抑制性颠覆为促免疫原性的局部治疗方式可引发全身性抗肿瘤免疫应答，诱导直接治疗以及未治疗的远端肿瘤消退。产生强大的抗肿瘤T细胞应答的关键是肿瘤微环境中树突状细胞（DC）的活化。用触发各种模式识别受体的激动剂治疗对激活DC是非常有效的，但遭受严重的免疫相关的不良反应的诱导，这与它们的不利的PK/PD特征密切相关，导致全身免疫激活和细胞因子释放。在此，据报道，高效TLR 7/8激动剂的纳米颗粒缀合将免疫活化限制于肿瘤床及其前哨淋巴结，而不妨碍治疗性抗肿瘤功效。在机制水平上，证实了用纳米颗粒缀合的TLR 7/8激动剂局部治疗导致前哨淋巴结中DC的有效活化并促进肿瘤抗原特异性CD 8 T细胞的增殖。此外，证明了与抗PDL 1检查点抑制和Flt 3L（一种扩增和动员来自骨髓的DC的生长因子）组合后的治疗改善。这些发现为通过纳米医学策略进行局部肿瘤工程提供了合理的基础，这些策略提供了对免疫激活的空间控制。
Localized therapeutic modalities that subvert the tumor microenvironment from immune-suppressive to pro-immunogenic can elicit systemic antitumor immune responses that induce regression of directly treated as well as nontreated distal tumors. A key toward generating robust antitumor T cell responses is the activation of dendritic cells (DCs) in the tumor microenvironment. Treatment with agonists triggering various pattern recognition receptors is very efficient to activate DCs, yet suffers from the induction of serious immune-related adverse effects, which is closely linked to their unfavorable PK/PD profile causing systemic immune activation and cytokine release. Here, it is reported that nanoparticle conjugation of a highly potent TLR7/8 agonist restricts immune activation to the tumor bed and its sentinel lymph nodes without hampering therapeutic antitumor efficacy. On a mechanistic level, it is confirmed that localized treatment with a nanoparticle-conjugated TLR7/8 agonist leads to potent activation of DCs in the sentinel lymph nodes and promotes proliferation of tumor antigen-specific CD8 T cells. Furthermore, therapeutic improvement upon combination with anti-PDL1 checkpoint inhibition and Flt3L, a growth factor that expands and mobilizes DCs from the bone marrow, is demonstrated. The findings provide a rational base for localized tumor engineering by nanomedicine strategies that provide spatial control over immune-activation.