Key Points Enhanced Ag cross-presentation by naringenin is due to moderate ROS induction. Naringenin potentially facilitates therapeutic vaccines against cancers or viruses. Flavonoids manipulate intracellular ROS, making them excellent immunomodulators. Dendritic cells (DCs) can internalize and cross-present exogenous Ags to CD8+ T cells for pathogen or tumor cell elimination. Recently, growing evidences suggest the possible immunoregulatory role of flavonoids through modulating the Ag presentation of DCs. In this study, we report that naringenin, a grapefruit-derived flavonoid, possesses the ability to increase the Ag cross-presentation in both murine DC line DC2.4 as well as bone marrow–derived DCs, and naringenin-induced moderate intracellular oxidative stress that contributed to the disruption of lysosomal membrane enhanced Ag leakage to cytosol and cross-presentation. Moreover, in a murine colon adenocarcinoma model, naringenin induced more CD103+ DCs infiltration into tumor and facilitated the activation of CD8+ T cells and strengthened the performance of therapeutic E7 vaccine against TC-1 murine lung cancer. Our investigations may inspire novel thoughts for vaccine design and open a new field of potential applications of flavonoids as immunomodulators to improve host protection against infection and tumor.

中文翻译：

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柚皮素通过促进抗原交叉呈递增强治疗性疫苗的抗肿瘤作用

关键点 柚皮素增强的 Ag 交叉呈递是由于适度的 ROS 诱导。柚皮素有可能促进针对癌症或病毒的治疗性疫苗。类黄酮操纵细胞内 ROS，使它们成为极好的免疫调节剂。树突状细胞 (DC) 可以将外源性抗原内化并交叉呈递给 CD8+ T 细胞，以消除病原体或肿瘤细胞。最近，越来越多的证据表明类黄酮可能通过调节 DC 的 Ag 呈递发挥免疫调节作用。在这项研究中，我们报道柚皮素衍生的黄酮类化合物柚皮素具有增加鼠 DC 系 DC2.4 和骨髓衍生 DC 中 Ag 交叉呈递的能力，柚皮素诱导的中度细胞内氧化应激导致溶酶体膜的破坏，增强了 Ag 向细胞质的渗漏和交叉呈递。此外，在鼠结肠腺癌模型中，柚皮素诱导更多的 CD103+ DC 浸润到肿瘤中，促进 CD8+ T 细胞的活化，并增强了治疗性 E7 疫苗对 TC-1 鼠肺癌的性能。我们的研究可能会激发疫苗设计的新思路，并为类黄酮作为免疫调节剂的潜在应用开辟新领域，以改善宿主对感染和肿瘤的保护。柚皮素诱导更多的 CD103+ DCs 浸润到肿瘤中，促进 CD8+ T 细胞的活化，并增强了治疗性 E7 疫苗针对 TC-1 鼠肺癌的性能。我们的研究可能会激发疫苗设计的新思路，并为类黄酮作为免疫调节剂的潜在应用开辟新领域，以改善宿主对感染和肿瘤的保护。柚皮素诱导更多的 CD103+ DCs 浸润到肿瘤中，促进 CD8+ T 细胞的活化，并增强了治疗性 E7 疫苗针对 TC-1 鼠肺癌的性能。我们的研究可能会激发疫苗设计的新思路，并为类黄酮作为免疫调节剂的潜在应用开辟新领域，以改善宿主对感染和肿瘤的保护。