A novel cancer immunotherapy based on the combination of a synthetic carbohydrate-pulsed dendritic cell vaccine and glycoengineered cancer cells
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Lei Qiu1,*, Jie Li1,*, Shichong Yu1, Qianli Wang2, Yinghua Li1, Zhenlin Hu1, Qiuye Wu1, Zhongwu Guo2, Junping Zhang1
1College of Pharmacy, Second Military Medical University, Shanghai 200433, China
2Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
*These authors have contributed equally to this work
Junping Zhang, e-mail: firstname.lastname@example.org
Zhongwu Guo, e-mail: email@example.com
Keywords: Cancer immunotherapy, Tumor-associated carbohydrate antigen, GM3 antigen, Cell metabolic glycoengineering
Abbreviations: TACAs: Tumor-associated carbohydrate antigens; KLH: Keyhole limpet hemoeyanin; HSA: Human serum albumin; CTL: Cytotoxic T lymphocyte
Received: October 20, 2014 Accepted: December 13, 2014 Published: March 04, 2015
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.
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