An indoleamine 2, 3-dioxygenase siRNA nanoparticle-coated and Trp2-displayed recombinant yeast vaccine inhibits melanoma tumor growth in mice
An indoleamine 2, 3-dioxygenase siRNA nanoparticle-coated and Trp2-displayed recombinant yeast vaccine inhibits melanoma tumor growth in mice
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吲哚胺 2, 3-双加氧酶 siRNA 纳米颗粒包被和 Trp2 展示的重组酵母疫苗可抑制小鼠黑色素瘤生长
DOI：
10.1016/j.jconrel.2018.01.013
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通讯作者：
Rui-tian Liu
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作者：
Dongqun Liu;Shuai Lu;Ling-xiao Zhang;Mei Ji;Shu-ying Liu;Shao-wei Wang;Rui-tian Liu
治疗性疫苗是癌症治疗中一种有前途的方法。但肿瘤相关抗原肽的免疫原性较弱，癌症患者往往存在免疫抑制和耐受的特点，导致免疫治疗的效率较低。我们在这里成功开发了吲哚胺 2, 3-双加氧酶 (IDO) siRNA 纳米颗粒涂层和酪氨酸酶相关蛋白 2 (Trp2) 展示的重组酿酒酵母 (YCP)。 YCPs带有正电荷，直径约为5μm，可被APC细胞选择性吞噬。 YCP递送的siRNA和Trp2成功逃离吞噬体，有效抑制DC中IDO的表达，促进T细胞针对Trp2的免疫反应，增加促炎细胞因子如IFN-γ、TNF-α和IL-6的分泌，并减少调节性T细胞的产生。此外，YCPs 通过减轻免疫耐受和促进 Trp2 特异性 CD8+ T 细胞免疫反应，显着抑制黑色素瘤生长。这些结果表明，酿酒酵母作为同时递送IDO-siRNA和Trp2表位肽的联合免疫治疗平台是一种有前途的黑色素瘤治疗疫苗系统。
Therapeutic vaccine is a promising approach in cancer therapy. But tumor-associated antigen peptides have weak immunogenicity and cancer patients are often characterized by immunosuppression and tolerance, leading to less efficiency of immunotherapy. We here successfully developed indoleamine 2, 3-dioxygenase (IDO) siRNA nanoparticle-coated and tyrosinase-related protein 2 (Trp2)-displayed recombinant Saccharomyces cerevisiae (YCP). YCPs had positive charges with a diameter of approximately 5μm, resulting in selective phagocytosis by APC cells. YCP-delivered siRNA and Trp2 successfully escaped from phagosomes, efficiently inhibited IDO expression in DCs, promoted the immune reaction of T cell against Trp2, increased the secretion of proinflammatory cytokines such as IFN-γ,TNF-α, and IL-6, and decreased the generation of regulatory T cell. Moreover, YCPs significantly inhibited melanoma tumor growth by alleviating immune tolerance and promoting Trp2-specific CD8+ T cell immune response. These results suggest that Saccharomyces cerevisiae as a combined immunotherapeutic platform to simultaneously delivery IDO-siRNA and Trp2 epitope peptide is a promising vaccine system for melanoma treatment.