SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, School of Chemical Engineering , Sungkyunkwan University (SKKU) , 2066 Seobu-ro , Jangan-gu, Suwon , Gyeonggi-do 16419 , Republic of Korea.
New Drug Development Center , Osong Medical Innovation Foundation , 123 Osongsaengmyeong-ro , Cheongju , Chungcheongbuk-do 28160 , Republic of Korea.
ACS Nano. 2019 Nov 26;13(11):12671-12686. doi: 10.1021/acsnano.9b04207. Epub 2019 Oct 11.
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 (, immunostimulation and reprogramming of immunosuppression) of small molecule-based Toll-like receptor 7/8 agonists. Local 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-α and IFN-β), 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).
当前癌症免疫疗法的疗效较低与非免疫原性和免疫抑制性肿瘤微环境（TME）有关。为了克服这些限制，对抗肿瘤淋巴细胞进行免疫启动和重新编程 TME 中的免疫抑制因子都是必要的。在这里，我们提出了一种基于纳米乳液（NE）的免疫治疗平台，它不仅可以调节肿瘤诱导的抑制作用，还可以诱导有效的细胞介导的免疫反应以促进 T 细胞增殖。多功能 NE 可以通过整合 NE 作为递送系统的功效和基于小分子的 Toll 样受体 7/8 激动剂的多方面免疫调节特性（免疫刺激和免疫抑制的重编程）来制造。用负载 TLR7/8 激动剂的 NE 佐剂的肿瘤抗原（蛋白和肽）对黑色素瘤和宫颈肿瘤模型进行局部疫苗接种[NE（TLR7/8a）]，可募集和激活先天免疫细胞、淋巴细胞浸润和肿瘤相关 M2 巨噬细胞的极化，从而抑制肿瘤生长并延长原发性和再挑战肿瘤模型的存活时间。抗体耗竭实验还表明，巨噬细胞、I 型 IFN（IFN-α 和 IFN-β）、CD8 T 细胞和 NK1.1 细胞有助于 NE（TLR7/8a）的抗肿瘤作用。NE（TLR7/8a）治疗诱导的抗肿瘤淋巴细胞和免疫抑制性 TME 重编程的组合引发了与免疫检查点阻断治疗（抗 PD-1 和抗 PD-L1）的协同抗肿瘤免疫反应。
