METHODS: A novel biomimetic codelivery system (MCM@UN) was constructed by MOF nanoparticles UiO-66 loading with a bromodomain-containing protein 4 (BRD4) inhibitor and then coated with the membrane vesicles of homologous cancer cells that embedding the 18 C lipid tail of 3M-052 (M). The antitumor immune ability and tumor suppressive effect of MCM@UN were evaluated in a mouse model of triple-negative breast cancer (TNBC) and in vitro. The tumor immune microenvironment was analyzed by multicolor immunofluorescence staining.
RESULTS: In vitro and in vivo data showed that MCM@UN specifically targeted to TNBC cells and was superior to the free drug in terms of tumor growth inhibition and antitumor immune activity. In terms of mechanism, MCM@UN blocked BRD4 and PD-L1 to prompt dying tumor cells to disintegrate and expose tumor antigens. The disintegrated tumor cells released damage-associated molecular patterns (DAMPs), recruited dendritic cells (DCs) to efficiently activate CD8+ T cells to mediate effective and long-lasting antitumor immunity. In addition, TLR7/8 agonist on MCM@UN enhanced lymphocytes infiltration and immunogenic cell death and decreased regulatory T-cells (Tregs). On clinical specimens, we found that mature DCs infiltrating tumor tissues of TNBC patients were negatively correlated with the expression of BRD4, which was consistent with the result in animal model.
CONCLUSIONS: MCM@UN specifically targeted to TNBC cells and remodeled tumor immune microenvironment to inhibit malignant behaviors of TNBC.
方法:通过MOF纳米颗粒UiO-66加载含溴结构域蛋白4(BRD4)抑制剂,然后用包埋3M-052(M)的18C脂质尾的同源癌细胞的膜囊泡包被,构建了一种新型的仿生共递送系统(MCM@UN)。在三阴性乳腺癌(TNBC)小鼠模型中和体外评估了MCM@UN的抗肿瘤免疫能力和肿瘤抑制作用。通过多色免疫荧光染色分析肿瘤免疫微环境。
结果:体外和体内数据表明,MCM@UN特异性靶向TNBC细胞,在肿瘤生长抑制和抗肿瘤免疫活性方面优于游离药物。在机制方面,MCM@UN阻断了BRD4和PD-L1,以促使垂死的肿瘤细胞分解并暴露肿瘤抗原。解体的肿瘤细胞释放损伤相关分子模式(DAMPs),招募树突状细胞(DCs)有效激活CD8+T细胞介导有效和持久的抗肿瘤免疫。此外,MCM@UN上的TLR7/8激动剂增强淋巴细胞浸润和免疫原性细胞死亡并减少调节性T细胞(Tregs)。在临床标本上,我们发现TNBC患者成熟DC浸润肿瘤组织与BRD4的表达呈负相关,这与动物模型的结果一致。
结论:MCM@UN特异性靶向TNBC细胞,重塑肿瘤免疫微环境,抑制TNBC的恶性行为。