Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
School of Pharmaceutical Sciences, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China.
Acta Biomater. 2022 Jul 15;147:366-376. doi: 10.1016/j.actbio.2022.05.022. Epub 2022 May 16.
Immune response is initiated by dendritic cells (DCs), where the cross-presentation of antigens by DCs determines the activating of cytotoxic T cells. However, the efficacy of DCs-initiated immune response is governed by multiple (cascade) steps of immunogenic cell death (ICD), recruitment of DCs, and cross-presentation of DCs. It is urgent but challenging to achieve a platform for simultaneously regulating these multiple steps, amplifying the immune response against tumors. Herein, we reported a photodynamic nanodrug enabling simultaneous regulation of these multiple steps for realizing powerful immune response. The nanodrug was designed by the co-assembling of chlorin e6 (Ce6), celecoxib and 6-thio-2'-deoxyguanosine (6-thio-dG). In our nanodrug, Ce6 enables induction of ICD, while celecoxib down-regulates the prostaglandin E2 (PGE2) for promoting recruitment of DCs enabled by chemokine CCL5 produced from natural killer (NK) cells. Moreover, 6-thio-dG triggers DNA damages in the tumor cells, which in turn activates STING/interferon I pathway for enhancing the cross-presentation ability of DCs. Therefore, an amplified immune therapeutic effect against tumors is achieved, thanks to the simultaneous regulation of these multiple steps. The nanodrug effectively inhibits tumor growth and postoperative recurrence, demonstrating a new approach for boosting immune response initiated by DCs in cancer therapy. STATEMENT OF SIGNIFICANCE: The dendritic cells (DCs)-initiated immune response against tumors is dominated by multiple (cascade) steps including the process of (I) immunogenic cell death (ICD), (II) recruitment of DCs, and (III) cross-presentation of antigens by DCs. Based on this, it is urgent to design a nanoplatform enabling simultaneous regulation of these multiple steps for achieving a potent therapeutic efficacy. A carrier-free photodynamic nanodrug, engineered by a co-assembling approach, was designed to regulate DCs for realizing a powerful DCs-initiated immune response against tumors, thanks to the simultaneous regulation of the above multiple steps. Our nanodrug demonstrated a boosted immune response against tumors, powerfully suppressing primary/abscopal tumor growth and postoperative recurrence, which offers a conceptually innovative strategy for amplifying immunity against tumors.
免疫反应是由树突状细胞 (DCs) 启动的，其中 DCs 对抗原的交叉呈递决定了细胞毒性 T 细胞的激活。然而，DCs 启动的免疫反应的效果受到免疫原性细胞死亡 (ICD)、DCs 的募集和 DCs 的交叉呈递的多个 (级联) 步骤的控制。实现一个同时调节这些多个步骤的平台，以增强对肿瘤的免疫反应是当务之急，但具有挑战性。在这里，我们报道了一种光动力纳米药物，该药物能够同时调节这些多个步骤，以实现强大的免疫反应。该纳米药物是通过氯乙酮 (Ce6)、塞来昔布和 6-硫代-2'-脱氧鸟苷 (6-thio-dG) 的共组装设计的。在我们的纳米药物中，Ce6 能够诱导 ICD，而塞来昔布下调前列腺素 E2 (PGE2)，以促进自然杀伤 (NK) 细胞产生的趋化因子 CCL5 促进 DCs 的募集。此外，6-thio-dG 在肿瘤细胞中引发 DNA 损伤，进而激活 STING/干扰素 I 通路，增强 DCs 的交叉呈递能力。因此，由于这些多个步骤的同时调节，实现了对肿瘤的增强免疫治疗效果。该纳米药物有效地抑制肿瘤生长和术后复发，为癌症治疗中增强 DC 启动的免疫反应提供了一种新方法。
肿瘤的树突状细胞 (DCs) 启动的免疫反应受多个 (级联) 步骤主导，包括以下过程：(I)免疫原性细胞死亡 (ICD)、(II)DCs 的募集和 (III)DCs 对抗原的交叉呈递。基于此，设计一个能够同时调节这些多个步骤的纳米平台对于实现有效的治疗效果是紧迫的。通过共组装方法设计了一种无载体的光动力纳米药物，用于调节 DCs，以实现强大的针对肿瘤的 DCs 启动的免疫反应，这得益于对上述多个步骤的同时调节。我们的纳米药物显示出对肿瘤的增强免疫反应，有力地抑制了原发性/转移性肿瘤的生长和术后复发，为增强对肿瘤的免疫提供了一种概念上的创新策略。
