State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
J Control Release. 2018 Mar 10;273:1-12. doi: 10.1016/j.jconrel.2018.01.013. Epub 2018 Feb 2.
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 cells. 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.
治疗性疫苗是癌症治疗中一种很有前途的方法。但肿瘤相关抗原肽的免疫原性较弱，而癌症患者往往具有免疫抑制和耐受的特点，导致免疫治疗效率较低。我们成功地开发了色氨酸 2,3-双加氧酶（IDO）siRNA 纳米颗粒包被和酪氨酸相关蛋白 2（Trp2）展示的重组酿酒酵母（YCP）。YCP 带正电荷，直径约为 5μm，导致 APC 细胞的选择性吞噬。YCP 递送的 siRNA 和 Trp2 成功地从吞噬体中逃逸，有效地抑制了 DC 中的 IDO 表达，促进了 T 细胞对 Trp2 的免疫反应，增加了 IFN-γ、TNF-α 和 IL-6 等促炎细胞因子的分泌，并减少了调节性 T 细胞的产生。此外，YCP 通过减轻免疫耐受和促进 Trp2 特异性 CD8 T 细胞免疫反应，显著抑制了黑色素瘤肿瘤的生长。这些结果表明，酿酒酵母作为一种联合免疫治疗平台，同时递送 IDO-siRNA 和 Trp2 表位肽，是一种很有前途的黑色素瘤治疗疫苗系统。
