新型纳米材料FP-NPs通过上调IRF-8重编程MDSC抑制黑色素瘤肺转移的机制研究

Metastatic melanoma is extremely malignant, and the immunosuppression mediated by myeloid-derived suppressor cells (MDSC) is a major barrier to its effective immunotherapy. Until now, there is no effective therapy for it. We have prepared a novel nanomaterial FP-NPs, which has been found to recruit and polarize macrophages to M1 phenotype for pulmonary metastatic melanoma regression. M-MDSC is known to be a precursor of macrophages, and interferon regulatory factor-8 (IRF-8) positively regulates the production of M-MDSC. Interestingly, FP-NPs also promoted the differentiation of MDSC into M-MDSC and then polarized it to M1 macrophages with upregulation of IRF-8. Thus we put forward a hypothesis that FP-NPs has an anti-metastatic effect of melanoma by up-regulating the expression of IRF-8 for MDSC reprogramming. This project will evaluate the therapeutic effect of FP-NPs on melanoma lung metastasis by reprogramming MDSC, analyze the relationship between the expression of IRF-8 regulated by FP-NP and the polarization of MDSC to M1 macrophages, and explore the mechanism of which FP-NPs reprograms MDSC to M1 macrophages by upregulating the expression of IRF-8. This will be benefit to propose novel strategies and theories for clinical treatment of metastatic melanoma.

转移性黑色素瘤恶性程度极高，由髓源抑制性细胞（MDSC）介导的免疫抑制是其有效治疗的主要障碍，目前尚无有效的治疗方法。我们前期制备了一种新型纳米材料FP-NPs，发现其可促进巨噬细胞募集并向M1型极化，抑制黑色素瘤肺转移。已知M-MDSC是巨噬细胞的前体，干扰素调节因子-8（IRF-8）正向调控M-MDSC的产生。有趣的是，我们发现FP-NPs可促进MDSC向M-MDSC分化进而向M1型巨噬细胞极化，并上调IRF-8基因的表达。由此推测：FP-NPs可能通过调控IRF-8的表达重编程MDSC向M1型巨噬细胞极化而抑制黑色素瘤肺转移。本项目将确定FP-NPs 重编程MDSC对黑色素瘤肺转移的疗效；分析FP-NP调控IRF-8表达与MDSC向M1型巨噬细胞极化的关系；探索FP-NPs通过IRF-8重编程MDSC向M1型巨噬细胞极化的机制；为转移性黑色素瘤的临床治疗提出新的策略和理论参考。

转移性黑色素瘤是一种高度恶性的肿瘤，由髓源性抑制细胞（MDSC）介导的免疫抑制作用不仅会促进转移性黑色素瘤的恶性进展，而且会影响转移性黑色素瘤的有效免疫治疗。纳米技术为靶向MDSC细胞提供了新的治疗策略。本研究优化制备了一种由纳米氧化铁（Ferumoxytol）和TLR3激动剂poly(I:C)组成的新型纳米粒子FP-NPs，评估了该纳米粒子对小鼠肺转移黑色素瘤治疗的影响及其潜在分子机制。体内研究结果显示，FP-NPs能够显著抑制转移性黑色素瘤的进展，并减少小鼠肺组织、脾脏和骨髓中的MDSC细胞数量。体内外研究结果显示，FP-NPs可显著减少G-MDSC细胞数量，并促进M-MDSC细胞向抗肿瘤M1型巨噬细胞分化。转录组测序结果表明FP-NPs显著改变了与免疫相关的基因表达。综合GO分析、KEGG富集分析和qRT-PCR结果，FP-NPs可能通过上调髓系细胞分化相关基因Irf7的表达，激活干扰素β相关信号通路，从而下调G-MDSC细胞数量，促进M-MDSC细胞向M1巨噬细胞分化，抑制肺转移黑色素瘤。这些研究结果表明FP-NPs是一种具有调节髓系细胞功能的新型免疫-纳米材料，能够调控MDSC细胞向M1型巨噬细胞分化，有望为转移性黑色素瘤的临床治疗提供新的思路和理论参考。