Qiu Lei, Li Jie, Yu Shichong, Wang Qianli, Li Yinghua, Hu Zhenlin, Wu Qiuye, Guo Zhongwu, Zhang Junping
College of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States.
Oncotarget. 2015 Mar 10;6(7):5195-203. doi: 10.18632/oncotarget.2908.
Immune tolerance to tumor-associated carbohydrate antigens (TACAs) has severely restricted the usefulness of most TACAs. To overcome this problem, we selected a sialylated trisaccharide TACA, GM3, as a target antigen, and tested a new immunotherapeutic strategy by combining metabolic bioengineering with dendritic cell (DC) vaccination. We engineered cancer cells to express an artificial structure, N-phenylacetyl-D-neuraminic acid, in place of the natural N-acetyl-D-neuraminic acid of GM3 by using N-phenylacetyl-D-mannosamine (ManNPhAc) as a biosynthetic precursor. Next, we selectively targeted the bioengineered cancer cells by vaccination with DCs pulsed with the GM3 N-phenylacetyl derivative. Vaccination with GM3NPhAc-KLH-loaded DCs elicited robust GM3NPhAc-specific T cell-dependent immunity. The results showed that this strategy could significantly inhibit FBL3 tumor growth and prolong the survival of tumor-bearing mice; B16F10 lung metastases could also be reduced. These findings lay out a new strategy for overcoming immune tolerance to TACAs, such as GM3, for the development of effective tumor immunotherapies.
对肿瘤相关碳水化合物抗原（TACAs）的免疫耐受严重限制了大多数TACAs的应用。为克服这一问题，我们选择了一种唾液酸化三糖TACA，即GM3，作为靶抗原，并通过将代谢生物工程与树突状细胞（DC）疫苗接种相结合来测试一种新的免疫治疗策略。我们利用N-苯基乙酰-D-甘露糖胺（ManNPhAc）作为生物合成前体，对癌细胞进行工程改造，使其表达一种人工结构N-苯基乙酰-D-神经氨酸，以取代GM3的天然N-乙酰-D-神经氨酸。接下来，我们用负载GM3 N-苯基乙酰衍生物的DC进行疫苗接种，选择性地靶向经生物工程改造的癌细胞。用负载GM3NPhAc-KLH的DC进行疫苗接种可引发强大的GM3NPhAc特异性T细胞依赖性免疫。结果表明，该策略可显著抑制FBL3肿瘤生长并延长荷瘤小鼠的生存期；B16F10肺转移也可减少。这些发现为克服对GM3等TACAs的免疫耐受、开发有效的肿瘤免疫疗法奠定了新策略。
