Abstract：
Clinical translation of current cancer vaccine research has been hampered by limited antitumor immune responses due to inefficient antigen delivery and presentation, suboptimal DC and T cell activation. Biomaterial-based nanovaccine offers targeted antigen delivery, protection from degradation in vivo, and prolonged tumor therapeutic efficacy. This study introduces a lipid-coated deoxycholic acid-survivin nanoassembly (DA-L-DSA). Survivin, overexpressed in several cancer cells and involved in cancer cell growth and immune evasion, is selected as a tumor-associated antigen. An major histocompatibility complex class I binding epitope of survivin is engineered into the nanoassembly. R848, TLR 7/8 agonist, and SD-208, TGF-beta receptor1 kinase inhibitor, are coencapsulated into the nanoassembly as potent adjuvants to boost DC maturation and enhance antigen presentation. The DA-L-DSA effectively stimulates the maturation of dendritic cells, migrates into lymph nodes, and enhances T-cell activation and Th1 response. A substantial influx of cytotoxic T lymphocytes into primary tumors is observed in a murine melanoma model and demonstrates anti-metastatic effects in a spontaneous breast cancer metastasis model. Furthermore, DA-L-DSA exhibits a remarkable synergistic effect in the combination therapy with immune checkpoint inhibitors alleviating immunosuppressive tumor microenvironment. Taken together, these findings suggest DA-L-DSA as a promising immuno-therapeutic platform that could be applicable to diverse intractable cancers.
摘要：
由于抗原递送和呈递效率低下，目前癌症疫苗研究的临床转化受到抗肿瘤免疫反应有限的阻碍。次优的DC和T细胞激活。基于生物材料的纳米疫苗提供靶向抗原递送，保护免受体内降解，和延长肿瘤治疗效果。本研究引入了脂质包被的脱氧胆酸-存活素纳米组装体(DA-L-DSA)。幸存者,在几种癌细胞中过表达，并参与癌细胞生长和免疫逃避，被选为肿瘤相关抗原。survivin的主要组织相容性复合物I类结合表位被工程化到纳米组装体中。R848，TLR7/8激动剂，和SD-208，TGF-β受体1激酶抑制剂，共包封到纳米组装体中作为有效的佐剂以促进DC成熟和增强抗原呈递。DA-L-DSA有效刺激树突状细胞的成熟，迁移到淋巴结，并增强T细胞活化和Th1应答。在鼠黑素瘤模型中观察到细胞毒性T淋巴细胞大量流入原发性肿瘤,并在自发性乳腺癌转移模型中证明了抗转移作用。此外，DA-L-DSA在与免疫检查点抑制剂的联合治疗中表现出显著的协同作用,从而减轻免疫抑制性肿瘤微环境。一起来看,这些研究结果表明,DA-L-DSA是一种有前景的免疫治疗平台,可适用于多种顽固性癌症.
