Lyophilizable and Multifaceted Toll-like Receptor 7/8 Agonist-Loaded Nanoemulsion for the Reprogramming of Tumor Microenvironments and Enhanced Cancer Immunotherapy
Lyophilizable and Multifaceted Toll-like Receptor 7/8 Agonist-Loaded Nanoemulsion for the Reprogramming of Tumor Microenvironments and Enhanced Cancer Immunotherapy
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DOI：
10.1021/acsnano.9b04207
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发表时间：
2019-11-01
期刊：
影响因子：
17.1
通讯作者：
Lim, Yong Taik
中科院分区：
文献类型：
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作者：
Kim, Sun-Young;Kim, Sohyun;Lim, Yong Taik
目前肿瘤免疫治疗的低疗效与非免疫原性和免疫抑制性肿瘤微环境（TMEs）有关。为了克服这些限制，抗肿瘤淋巴细胞的免疫启动和TMEs中免疫抑制因子的重编程都是必不可少的。在这里，我们提出了一种基于纳米乳（NE）的免疫治疗平台，它不仅可以调节肿瘤诱导的抑制，还可以诱导有效的细胞介导的T细胞增殖免疫反应。多功能NEs可以通过整合NEs作为递送系统的功效和基于小分子toll样受体7/8激动剂的多方面免疫调节特性（即免疫刺激和免疫抑制重编程）来制造。用肿瘤抗原（蛋白和肽）佐剂NE加载TLR7/8激动剂[NE (TLR7/8a)]局部原位接种黑色素瘤和颈部肿瘤模型，诱导先天免疫细胞的募集和激活，淋巴细胞的浸润，肿瘤相关M2巨噬细胞的极化，从而抑制肿瘤生长，延长肿瘤生存期。抗体消耗实验也表明，巨噬细胞、I型IFN （IFN- α和IFN- β）、CD8(+) T细胞和NK1.1（+）细胞参与了NE （TLR7/8a）的抗肿瘤作用。抗肿瘤淋巴细胞与NE （TLR7/8a）治疗诱导的免疫抑制性TMEs重编程结合，可与免疫检查点阻断疗法（抗pd -1和抗pd - l1）协同产生抗肿瘤免疫应答。
The low therapeutic efficacy of current cancer immunotherapy is related to nonimmunogenic and immunosuppressive tumor microenvironments (TMEs). To overcome these limitations, both the immune priming of antitumoral lymphocytes and the reprogramming of immunosuppressive factors in TMEs are essential. Here, we suggest a nanoemulsion (NE)-based immunotherapeutic platform that can not only modulate tumor-induced suppression but also induce an effective cell-mediated immune response for T cell proliferation. Multifunctional NEs can be fabricated by integrating the efficacy of NEs as delivery systems and the multifaceted immunomodulation characteristics (i.e., immunostimulation and reprogramming of immunosuppression) of small molecule-based Toll-like receptor 7/8 agonists. Local in situ vaccination of melanoma and cervical tumor models with tumor antigens (protein and peptide) adjuvanted with NE loaded with TLR7/8 agonists [NE (TLR7/8a)] induced the recruitment and activation of innate immune cells, infiltration of lymphocytes, and polarization of tumor-associated M2 macrophages, which resulted in inhibition of tumor growth and prolonged survival in both primary and rechallenged tumor models. Antibody-depletion experiments also suggested that macrophages, type I IFN (IFN-alpha and IFN-beta), CD8(+) T cells, and NK1.1(+) cells contributed to the antitumor effect of NE (TLR7/8a). The combination of antitumoral lymphocytes and reprogramming of immunosuppressive TMEs induced by NE (TLR7/8a) treatment evoked a synergistic antitumor immune response with immune checkpoint blockade therapy (anti-PD-1 and anti-PD-L1).