Nano-delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in desmoplastic melanoma.
Nano-delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in desmoplastic melanoma.
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DOI：
10.7150/thno.24821
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发表时间：
2018
期刊：
影响因子：
12.4
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Hou L;Liu Q;Shen L;Liu Y;Zhang X;Chen F;Huang L
基本原理：肿瘤相关成纤维细胞（TAF）在抑制性免疫肿瘤微环境（TME）中发挥关键作用，影响免疫治疗的疗效。为了克服这一治疗障碍，我们开发了一种纳米乳剂（NE）制剂，将抗纤维化药物fraxinellone（Frax）递送至TAF，作为逆转促纤维增生性黑色素瘤的免疫抑制性TME的方法。方法：采用超声乳化法制备Frax NE。采用免疫荧光染色、Masson三色染色和western blot分析评价抑瘤效果。流式细胞术检测肿瘤和淋巴结中免疫细胞的数量。结果如下：这种粒径约为145 nm的Frax NE在全身给药后可以有效地在肿瘤部位蓄积，并被TAF和肿瘤细胞摄取。Frax NE静脉给药后，观察到TAF和基质沉积显著减少，Frax NE治疗还重塑了肿瘤免疫微环境，如TME中自然杀伤细胞、细胞毒性T细胞（CTL）增加以及调节性B细胞和髓源性抑制细胞减少所反映的。此外，Frax内斯治疗后，有效引发抗肿瘤免疫的干扰素γ（IFN-γ）的辅助性T细胞1（Th 1）细胞因子增强。抑制抗肿瘤免疫发展的转化生长因子-β（TGF-β）、趋化因子（C-C基序）配体2（CCL 2）和白细胞介素6（IL 6）减少。尽管Frax NE显示出对肿瘤生长的抑制作用，但这种单药治疗仅能达到部分抗肿瘤疗效，并且在停止给药后，肿瘤生长效应不能长期维持。因此，将肿瘤特异性肽疫苗与Frax内斯组合。该组合导致增强的肿瘤特异性T细胞浸润，激活肿瘤细胞表面上的死亡受体，并诱导增加的凋亡性肿瘤细胞死亡。结论：总的来说，Frax NE联合肿瘤特异性肽疫苗可能是重塑纤维化TME的有效和安全的策略，从而增强免疫应答激活，从而延长晚期促纤维增生性黑色素瘤的疗效。
Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy. To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of desmoplastic melanoma. Methods: Frax NE was prepared by an ultrasonic emulsification method. The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis. Immune cell populations in tumor and LNs were detected by flow cytometry. Results: This Frax NE, with a particle size of around 145 nm, can efficiently accumulate in the tumor site after systemic administration and was taken up by TAFs and tumor cells. A significant decrease in TAFs and stroma deposition was observed after intravenous administration of Frax NE, and Frax NE treatment also remolded the tumor immune microenvironment, as was reflected by an increase of natural-killer cells, cytotoxic T cells (CTLs) as well as a decrease of regulatory B cells, and myeloid-derived suppressor cells in the TME. In addition, after treatment by Frax NEs, T helper 1 (Th1) cytokines of interferon gamma (IFN-γ), which effectively elicit anti-tumor immunity, were enhanced. Transforming growth factor-β (TGF-β), chemokine (C-C motif) ligand 2 (CCL2) and interleukin 6 (IL6), which inhibit the development of anti-tumor immunity, were reduced. Although Frax NE demonstrated an inhibitory effect on tumor growth, this mono-therapy could only achieve partial antitumor efficacy, and the tumor growth effect was not maintained long-term after dosing stopped. Therefore, a tumor-specific peptide vaccine was combined with Frax NEs. The combination led to enhanced tumor-specific T-cell infiltration, activated death receptors on the tumor cell surface, and induced increased apoptotic tumor cell death. Conclusion: Collectively, Frax NE combined with tumor-specific peptide vaccine might be an effective and safe strategy to remodel fibrotic TME, thereby enhancing immune response activation, resulting in a prolonged efficiency for advanced desmoplastic melanoma.