Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece.
Department of Medicine, Laboratory of Medical Biology and Genetics, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
Int J Nanomedicine. 2022 Sep 22;17:4449-4468. doi: 10.2147/IJN.S346341. eCollection 2022.
Tumor immunotherapy is a key therapeutic paradigm for the treatment of several malignancies. However, in metastatic lung cancer, classical immunotherapy regimes are ineffective due to regulatory T cell (Treg)-related immunosuppression and tumor relapse.
To address this issue, we designed specific biocompatible Treg-targeted nanocarriers (NCs) as a model of immune-based nanotherapy, in order to target Treg-related immunosuppression in the lung tumor microenvironment. This is achieved through the combination of Dasatinib and Epacadostat integrated into biodegradable nanosomes which can inhibit and reverse Treg-supporting immunosuppression. Flow cytometry and immunofluorescence analysis, PET/CT scan, PTT/PA imaging and the Balb/c tumor model were used to explore the anti-tumor effect of Treg-targeted NCs both in vitro and in vivo.
Findings reveal that NC treatment triggered substantial tumor cell apoptosis and drastically decreased tumor volume followed by downregulation of Ki-67 antigen expression, respectively. Drug circulation time was also increased as shown by biodistribution analysis accompanied by greater accumulation in lung and peripheral tissues. Intratumoral Th1 cytokines' expression was also increased, especially TNF-A, IL-12 by 42%, and IL-6 by 18% compared to PBS treatment. In addition, the presence of mature CD80/CD86dendritic cells (DCs) revealed T cell enrichment and a decline in MDSC infiltration and myeloid subsets. Interestingly, a significant decline of Gr/CD11b myeloid cell population in blood and tissue samples was also observed. This immune activation can be attributed to the enhanced PTT efficiency and tumor targeting ability of the nanospheres which under near infrared (NIR) exposure can prompt highly efficient tumor ablation. We also demonstrated their therapeutic efficacy against 4T1 metastatic breast cancer model. Additionally, the photothermal therapy in combination with PD-L1 checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors.
Overall, our findings present a novel nano-enabled platform for the inhibition of Treg-dependent immunosuppression in NSCLC and provide a novel nanotherapeutic strategy for the treatment of metastatic neoplasia.
肿瘤免疫疗法是治疗多种恶性肿瘤的关键治疗范例。然而，在转移性肺癌中，由于调节性 T 细胞（Treg）相关的免疫抑制和肿瘤复发，经典的免疫疗法无效。
为了解决这个问题，我们设计了特定的生物相容性 Treg 靶向纳米载体（NCs）作为免疫为基础的纳米治疗的模型，以靶向肺肿瘤微环境中的 Treg 相关免疫抑制。这是通过将达沙替尼和依帕卡度司他整合到可生物降解的纳米体中实现的，纳米体可以抑制和逆转 Treg 支持的免疫抑制。通过流式细胞术和免疫荧光分析、PET/CT 扫描、PTT/PA 成像和 Balb/c 肿瘤模型，在体外和体内研究了 Treg 靶向 NC 的抗肿瘤作用。
研究结果表明，NC 治疗触发了大量的肿瘤细胞凋亡，并显著降低了肿瘤体积，随后 Ki-67 抗原的表达也下调。通过生物分布分析也显示药物循环时间延长，同时在肺部和周围组织中的积累增加。肿瘤内 Th1 细胞因子的表达也增加，与 PBS 治疗相比，TNF-A、IL-12 分别增加了 42%，IL-6 增加了 18%。此外，成熟的 CD80/CD86 树突状细胞（DCs）的存在显示 T 细胞富集，髓样细胞浸润和髓样细胞亚群减少。有趣的是，还观察到血液和组织样本中 Gr/CD11b 髓样细胞群的显著下降。这种免疫激活可归因于纳米球的增强的 PTT 效率和肿瘤靶向能力，在近红外（NIR）暴露下可以促使高效的肿瘤消融。我们还证明了它们对 4T1 转移性乳腺癌模型的治疗效果。此外，光热疗法联合 PD-L1 检查点阻断疗法对原发性和远处肿瘤均具有长期的肿瘤控制作用。
总的来说，我们的研究结果为 NSCLC 中抑制 Treg 依赖性免疫抑制提供了一种新的基于纳米的平台，并为转移性肿瘤的治疗提供了一种新的纳米治疗策略。
