A novel cancer immunotherapy based on the combination of a synthetic carbohydrate-pulsed dendritic cell vaccine and glycoengineered cancer cells

Abstract

// Lei Qiu 1, * , Jie Li 1, * , Shichong Yu 1 , Qianli Wang 2 , Yinghua Li 1 , Zhenlin Hu 1 , Qiuye Wu 1 , Zhongwu Guo 2 , Junping Zhang 1 1 College of Pharmacy, Second Military Medical University, Shanghai 200433, China 2 Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States * These authors have contributed equally to this work Correspondence to: Junping Zhang, e-mail: jpzhang08@hotmail.com Zhongwu Guo, e-mail: zwguo@chem.wayne.edu 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 ABSTRACT 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.