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Immunogenicity and efficacy of a rationally designed vaccine against vascular endothelial growth factor in mouse solid tumor models

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Abstract

Vascular endothelial growth factor (VEGF) plays an important role in the progression of various cancers. The VEGF-specific antibody bevacizumab combined with chemotherapy was shown to significantly improve progression-free survival in certain cancers. However, repeated administration is necessary for effective suppression of VEGF, thereby making the therapy expensive and cumbersome. Thus, it is urgent to develop alternative reagents such as VEGF vaccines. Here we report that DTT-VEGF, a VEGF-based antigen consisting of the receptor-binding domain of VEGF and diphtheria toxin T domain (DTT), not only stimulated neutralizing antibody response, but also induced type 1 immune response as well as anti-tumor cytotoxic T lymphocytes in mice when administered with aluminum hydroxide adjuvant. The antibodies triggered by DTT-VEGF immunization inhibited the binding of VEGF to VEGF receptor and downregulated the serum VEGF levels in tumor-bearing mice. VEGF-specific IgG2a and IgG2b antibodies as well as type 1 cytokines were stimulated by DTT-VEGF vaccination. The splenocytes from DTT-VEGF-immunized mice showed cytotoxic activity against B16-F10 cells expressing VEGF. Extensive necrosis with severe hemorrhage and enhanced CD8+ T cell infiltration were observed in tumors from DTT-VEGF-immunized mice. The percentages of CD31+ vascular areas in the tumor sections from DTT-VEGF-immunized mice were significantly lower than those of control mice. DTT-VEGF significantly inhibited tumor growth in preventive and therapeutic vaccination settings in mouse models. Our data suggest that DTT is an effective antigen carrier to break immune self-tolerance and our vaccine design has potential to be used for human cancer therapy.

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Abbreviations

Alum:

Aluminum hydroxide

CFSE:

Carboxyfluorescein succinimidyl ester

CTLs:

Cytotoxic T lymphocytes

DCs:

Dendritic cells

DTT:

Diphtheria toxin T domain

GST:

Glutathione S-transferase

H&E:

Hematoxylin and eosin

IFA:

Incomplete Freund’s adjuvant

LDH:

Lactate dehydrogenase

mAbs:

Monoclonal antibodies

SEM:

Standard error of mean

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgements

This work was supported by National S and T major projects of China (Key Innovative Drug Development) (No. 2014ZX09101043), Shanghai Municipal Science and Technology Program (No. 14431904100), Shanghai Industry-Academia-Research Collaboration Program (No. CXY-2013-54), Medicine Science/Engineering Hybrid Project of Shanghai Jiao Tong University (No. YG2013MS09) and Specialized Research Fund for the Doctoral Program of Higher Education of China (SRFDP) (No. 20130073120110).

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Authors and Affiliations

  1. State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China

    Aizhang Xu, Li Zhang, Yangyang Chen, Zhibing Lin & Rongxiu Li

  2. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China

    Aizhang Xu, Li Zhang, Yangyang Chen, Zhibing Lin & Rongxiu Li

  3. Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China

    Rongxiu Li

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  1. Aizhang Xu
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Xu, A., Zhang, L., Chen, Y. et al. Immunogenicity and efficacy of a rationally designed vaccine against vascular endothelial growth factor in mouse solid tumor models. Cancer Immunol Immunother 66, 181–192 (2017). https://doi.org/10.1007/s00262-016-1928-0

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