Effective inhibition of melanoma tumorigenesis and growth via a new complex vaccine based on NY-ESO-1-alum-polysaccharide-HH2

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Abstract

Background

A safe and effective adjuvant plays an important role in the development of a vaccine. However, adjuvants licensed for administration in humans remain limited. Here, for the first time, we developed a novel combination adjuvant alum-polysaccharide-HH2 (APH) with potent immunomodulating activities, consisting of alum, polysaccharide of Escherichia coli and the synthetic cationic innate defense regulator peptide HH2.

Methods

The adjuvant effects of APH were examined using NY-ESO-1 protein-based vaccines in prophylactic and therapeutic models. We further determined the immunogenicity and anti-tumor effect of NY-ESO-1-APH (NAPH) vaccine using adoptive cellular/serum therapy in C57/B6 and nude mice. Cell-mediated and antibody-mediated immune responses were evaluated.

Results

The APH complex significantly promoted antigen uptake, maturation and cross-presentation of dendritic cells and enhanced the secretion of TNF-α, MCP-1 and IFN-γ by human peripheral blood mononuclear cells compared with individual components. Vaccination of NAPH resulted in significant tumor regression or delayed tumor progression in prophylactic and therapeutic models. In addition, passive serum/cellular therapy potently inhibited tumor growth of NY-ESO-1-B16. Mice treated with NAPH vaccine produced higher antibody titers and greater antibody-dependent/independent cellular cytotoxicity. Therefore, NAPH vaccination effectively stimulated innate immunity, and boosted both arms of the adaptive humoral and cellular immune responses to suppress tumorigenesis and growth of melanoma.

Conclusions

Our study revealed the potential application of APH complex as a novel immunomodulatory agent for vaccines against tumor refractory and growth.

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Most cited references 46

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Cancer/testis (CT) antigens: potential targets for immunotherapy.

Otavia Caballero, Yao-Tseng Chen (2009)

Cancer/testis (CT) antigens are protein antigens with normal expression restricted to adult testicular germ cells, and yet are aberrantly activated and expressed in a proportion of various types of human cancer. At least a subset of this group of antigens has been found to elicit spontaneous humoral and cell-mediated immune responses in cancer patients, raising the possibility that these antigens could be cancer vaccine targets. More than 100 CT antigen genes have been reported in the literature, with approximately 30 being members of multigene families on the X chromosome, so-called CT-X genes. Most CT-X genes are expressed at the spermatogonia stage of spermatogenesis, and their functions are mostly unknown. In cancer, the frequency of CT antigen expression is highly variable among different tumor types, but is more often expressed in high-grade late-stage cases in general. Cancer vaccine trials based on CT antigens MAGE-A3 and NY-ESO-1 are currently ongoing, and these antigens may also play a role in antigen-specific adoptive T-cell transfer and in the immunomodulation approach of cancer therapy.

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Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity.

G. Ng, Ping Zhang, Tracy Flach … (2011)

As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4(+) T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.

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Dietary modulation of immune function by beta-glucans.

Thomas J H Volman, Julian Ramakers, Jogchum Plat (2008)

The immune response can be modulated by nutrients like beta-glucans, which are glucose polymers that are major structural components of the cell wall of yeast, fungi, and bacteria, but also of cereals like oat and barley. There is a lot of structural variation in the beta-glucans from these different sources, which may influence their physiological functions. In this review the current status concerning possibilities to modulate immune function by beta-glucans is discussed. In vitro as well as in vivo studies in animals and humans show that especially beta-glucans derived from fungi and yeast have immune modulating properties. Most frequently evaluated are effects on leukocyte activity, which has been suggested to contribute to the increased resistance against infections observed after beta-glucan interventions. Although most studies supply the beta-glucans parenteral (e.g. intravenous or subcutaneous), also enteral administrated (dietary) beta-glucan influence the immune response. Although more human studies are needed, it is tempting to suggest that dietary beta-glucans may be a useful tool to prime the host immune system and increase resistance against invading pathogens.

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Author and article information

Contributors

Meng Li

Huashan Shi

Yandong Mu

Zichao Luo

Hailong Zhang

Yang Wan

Dongmei Zhang

Lian Lu

Ke Men

Yaomei Tian

Xiaozhe Wu

Xiaoyan Liu

Ying Pan

Yingzi Fan

Chaoheng Yu

Bailing Zhou

Rong Xiang

Xiancheng Chen

Li Yang

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central

ISSN (Electronic): 1476-4598

Publication date Collection: 2014

Publication date (Electronic): 28 July 2014

Volume: 13

Page: 179

Affiliations

[1 ]State Key Laboratory of Biotherapy / Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, PR China

[2 ]Department of Stomotology, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Chengdu, PR China

[3 ]Institute of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical College, Wenzhou, PR China

[4 ]Department of Immunology, Nankai University School of Medicine, Tianjin, PR China

Article

Publisher ID: 1476-4598-13-179

DOI: 10.1186/1476-4598-13-179

PMC ID: 4120012

PubMed ID: 25070035

SO-VID: fd3578df-01d8-4244-95aa-7cfb431799f9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Effective inhibition of melanoma tumorigenesis and growth via a new complex vaccine based on NY-ESO-1-alum-polysaccharide-HH2

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Abstract

Background

Methods

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Conclusions

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Karger: Dermatology

Most cited references 46

Cancer/testis (CT) antigens: potential targets for immunotherapy.

Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity.

Dietary modulation of immune function by beta-glucans.

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