Nanoparticle-delivered transforming growth factor-β siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment.
Nanoparticle-delivered transforming growth factor-β siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment.
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DOI：
10.1021/nn500216y
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发表时间：
2014-04-22
期刊：
影响因子：
17.1
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
--
作者：
Xu, Zhenghong;Wang, Yuhua;Zhang, Lu;Huang, Leaf
实现针对自身/肿瘤抗原的有效免疫应答和针对晚期肿瘤的有效治疗结果仍然是癌症免疫治疗的主要挑战。两种基于纳米颗粒的递送系统，脂质-磷酸钙（LCP）纳米颗粒（NP）和脂质体-鱼精蛋白-透明质酸（LPH）NP的特异性和效率为我们提供了解决这两个挑战的机会。甘露糖修饰的LCP NP将肿瘤抗原（Trp 2肽）和佐剂（CpG寡核苷酸）递送至树突状细胞，并引发有效的全身免疫应答，而不管宿主中肿瘤的存在或阶段。然而，这种疫苗在皮下同基因模型中对晚期B16 F10黑色素瘤的有效性较低。机制性随访研究表明，肿瘤微环境中免疫抑制性细胞因子（如TGF-β）水平升高可能是原因。我们通过沉默肿瘤细胞中的TGF-β策略性地增强LCP疫苗对晚期肿瘤的功效。使用LPH NP递送siRNA导致晚期肿瘤微环境中TGF-β的约50%敲低。与单独疫苗治疗相比，TGF-β下调增强了疫苗效力并抑制肿瘤生长52%，这是由于肿瘤浸润性CD 8 + T细胞水平增加和调节性T细胞水平降低。LCP疫苗系统诱导抗原特异性免疫应答和LPH NP靶向修饰肿瘤微环境的结合为机制研究和免疫策略开发提供了灵活而强大的平台。
Achievement of potent immunoresponses against self/tumor antigens and effective therapeutic outcome against advanced tumors remain major challenges in cancer immunotherapy. The specificity and efficiency of two nanoparticle-based delivery systems, lipid-calcium-phosphate (LCP) nanoparticle (NP) and liposome-protamine-hyaluronic acid (LPH) NP, provide us an opportunity to address both challenges. A mannose-modified LCP NP delivered both tumor antigen (Trp 2 peptide) and adjuvant (CpG oligonucleotide) to the dendritic cells and elicited a potent, systemic immune response regardless of the existence or the stage of tumors in the host. This vaccine was less effective, however, against later stage B16F10 melanoma in a subcutaneous syngeneic model. Mechanistic follow-up studies suggest that elevated levels of immune-suppressive cytokines within the tumor microenvironment, such as TGF-β, might be responsible. We strategically augment the efficacy of LCP vaccine on an advanced tumor by silencing TGF-β in tumor cells. The delivery of siRNA using LPH NP resulted in about 50% knockdown of TGF-β in the late stage tumor microenvironment. TGF-β down-regulation boosted the vaccine efficacy and inhibited tumor growth by 52% compared with vaccine treatment alone, as a result of increased levels of tumor infiltrating CD8+ T cells and decreased level of regulatory T cells. Combination of systemic induction of antigen-specific immune response with LCP vaccine and targeted modification of tumor microenvironment with LPH NP offers a flexible and powerful platform for both mechanism study and immunotherapeutic strategy development.
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影响因子：
11.2
作者：
Kim S;Buchlis G;Fridlender ZG;Sun J;Kapoor V;Cheng G;Haas A;Cheung HK;Zhang X;Corbley M;Kaiser LR;Ling L;Albelda SM
通讯作者：
Albelda SM
影响因子：
5.8
作者：
Vasievich, Elizabeth A.;Chen, Weihsu;Huang, Leaf
通讯作者：
Huang, Leaf
DOI：
10.4049/jimmunol.0802664
发表时间：
2009-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Liu Z;Kim JH;Falo LD Jr;You Z
通讯作者：
You Z
影响因子：
6.4
作者：
Grasso, Felicia;Negri, Donatella R. M.;Cara, Andrea
通讯作者：
Cara, Andrea
影响因子：
64.8
作者：
Mellman, Ira;Coukos, George;Dranoff, Glenn
通讯作者：
Dranoff, Glenn