Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China.
Pharm Res. 2020 May 31;37(6):109. doi: 10.1007/s11095-020-02838-4.
PURPOSE: Cancer-Immunity Cycle is a cascade of anticancer immune responses in the body that continues and fights against the cancer expansion. The Cancer-Immunity Cycle is halted by tumor cell immunosuppression of host T cell through programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) interactions that induce the functional suppression of tumor-reactive cytotoxic T cells and actively promotes the tumorigenesis via the mTOR signaling pathway.
METHODS: Here, we demonstrated that this Cycle could be enhanced by the synergistic knock down of PD-L1 through co-delivery of siRNA-PD-L1 (siPD-L1) and imatinib (IMT) in a liposomal nanoparticle.
RESULTS: The siPDIN effectively downregulated the protein expressions of PD-L1 and significantly knocked down the expression of p-S6k protein at in vitro and in vivo conditions which inhibited tumorigenic mTOR pathway. The combination-based siPDIN exhibited a significantly higher cytotoxic effect compared to that of individual anticancer agents. B16F10 cells treated with siPDIN exhibited a significantly higher cancer cell apoptosis (60%) compared to cocktail combination of siRNA+IMT (35%) analyzed by flow cytometer. Importantly, siPDIN significantly delayed the tumor growth with significantly lower tumor-specific growth rate than the animals treated with individual free IMT or siRNA. siPDIN produced a 3-fold higher IFN-γ compared to control in DLNs and 4-fold higher IFN-γ in spleens.
CONCLUSION: Overall, results revealed that the tumors treated with siPDIN restored the immunity of CTLs by potentially inhibiting the immune checkpoint interactions, suppressed the mTOR signaling pathway and exhibited an enhanced anticancer efficacy in melanoma.
目的：癌症免疫循环是体内抗癌免疫反应的级联反应，它会持续不断地对抗肿瘤的扩张。肿瘤细胞通过程序性细胞死亡受体 1（PD-1）和程序性细胞死亡配体 1（PD-L1）的相互作用抑制宿主 T 细胞的免疫抑制作用，从而阻止了癌症免疫循环，这种相互作用诱导了肿瘤反应性细胞毒性 T 细胞的功能抑制，并通过 mTOR 信号通路积极促进肿瘤发生。
方法：在这里，我们通过在脂质体纳米颗粒中共递送 siRNA-PD-L1（siPD-L1）和伊马替尼（IMT）来证明，这种循环可以通过协同敲低 PD-L1 来增强。
结果：siPDIN 有效地下调了 PD-L1 的蛋白表达，并在体外和体内条件下显著敲低了 p-S6k 蛋白的表达，从而抑制了致癌的 mTOR 通路。与单独使用抗癌药物相比，基于组合的 siPDIN 表现出更高的细胞毒性作用。通过流式细胞仪分析，用 siPDIN 处理的 B16F10 细胞表现出显著更高的癌细胞凋亡（60%），而 siRNA+IMT 的鸡尾酒组合仅为（35%）。重要的是，与单独使用游离 IMT 或 siRNA 治疗的动物相比，siPDIN 显著延迟了肿瘤生长，肿瘤特异性生长率显著降低。siPDIN 在 DLNs 中产生了 3 倍于对照的 IFN-γ，在脾脏中产生了 4 倍于对照的 IFN-γ。
结论：总的来说，结果表明，用 siPDIN 治疗的肿瘤通过潜在地抑制免疫检查点相互作用恢复了 CTL 的免疫功能，抑制了 mTOR 信号通路，并在黑色素瘤中表现出增强的抗癌疗效。
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