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Synergistic effect of programmed cell death protein 1 blockade and secondary lymphoid tissue chemokine in the induction of anti-tumor immunity by a therapeutic cancer vaccine

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An Erratum to this article was published on 24 November 2016

Abstract

The use of DNA vaccines has become an attractive approach for generating antigen-specific cytotoxic CD8+ T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be improved by using an adjuvant injected together with checkpoint antibodies. In the current study, we evaluated whether the therapeutic effects of a DNA vaccine encoding human papilloma virus type 16 (HPV-16) E7 can be enhanced by combined application of an immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway and secondary lymphoid tissue chemokine (SLC) also known as CCL21 adjuvant, in a mouse cervical cancer model. The therapeutic effects of the DNA vaccine in combination with CCL21 adjuvant plus PD-1 blockade was evaluated using a tumor growth curve. To further investigate the mechanism underlying the antitumor response, cytolytic and lymphocyte proliferation responses in splenocytes were measured using non-radioactive cytotoxicity and MTT assays, respectively. Vascular endothelial growth factor (VEGF) and IL-10 expression in the tumor and the levels of IFN-γ and IL-4 in supernatants of spleno-lymphocyte cultures were measured using ELISA. The immune efficacy was evaluated by in vivo tumor regression assay. The results showed that vaccination with a DNA vaccine in combination with the CCL21 adjuvant plus PD-1 blockade greatly enhanced cytotoxic T lymphocyte production and lymphocyte proliferation rates and greatly inhibited tumor progression. Moreover, the vaccine in combination with adjuvant and blockade significantly reduced intratumoral VEGF, IL-10 and splenic IL-4 but induced the expression of splenic IFN-γ. This formulation could be an effective candidate for a vaccine against cervical cancers and merits further investigation.

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Abbreviations

HPV:

Human papilloma virus

APC:

Antigen-presenting cell

CTL:

Cytolytic CD8+T lymphocyte

DC:

Dendritic cells

IFN- γ:

Interferon γ

IL-4:

Interleukin 4

VEGF:

Vascular endothelial growth factor

IL-10:

Interleukin 10

LDH:

Lactate dehydrogenase

MTT:

3[4,5-Dimethylthiazol-2-ll]-2,5-diphenyltetrazolium bromide, thiazolyl-blue

DMSO:

Dimethyl sulfoxide

OD:

Optical density

FBS:

Fetal bovine serum

RPMI:

1640 Roswell Park Memorial Institute (name of the medium)

Th:

T helper

PD-1:

Programmed death-1

SLC:

Secondary lymphoid tissue chemokine

TAA:

Tumor-associated antigen

TIL:

Tumor-infiltrating lymphocyte

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Acknowledgments

The authors would like to acknowledge Institute Pasteur of Iran and Golestan Medical University for the financial support. This project was extracted from a MSC thesis.

Author information

Authors and Affiliations

  1. Mashhad University of Medical Sciences, Mashhad, Iran

    Soheila Moeini

  2. Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran

    Mohsen Saeidi

  3. Department of Virology, Pasteur Institute of Iran, P.O.Box: 1316943551, Tehran, Iran

    Fatemeh Fotouhi & Amir Ghaemi

  4. Biotechnology and molecular medicine, Arak University of medical sciences, Arak, Iran

    Mahdieh Mondanizadeh

  5. Department of Pathology, School of Veterinary Medicine, Shahrekord University,  Shahrekord, Iran

    Sadegh Shirian

  6. Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran

    Alireza Mohebi

  7. Infectious Diseases Research Center, Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran

    Alireza Mohebi

  8. Institut für Physiologie I, Westfälische Wilhelms-Universität Münster, Robert-Koch-Strasse Münster, Germany

    Ali Gorji

  9. Shefa Neuroscience Research Center, Tehran, Iran

    Ali Gorji

Authors
  1. Soheila Moeini
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  4. Mahdieh Mondanizadeh
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  8. Amir Ghaemi
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Corresponding author

Correspondence to Amir Ghaemi.

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Funding

This study was supported by Institute Pasteur of Iran and Research Deputy at Golestan Medical University through Grant Project Number 157495.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The animal protocol used in this study was approved by the local animal ethics council of Golestan Ethics Committee of Golestan University of Medical Sciences (ethics number: et-157495). All experimental procedures involving mice were performed in accordance with the national experimental guidelines.

Additional information

The original version of this article was revised: “Unfortunately, the fourth author name “Mahdieh Mondanizadeh” was incorrectly published in this original version and the same is corrected here”.

An erratum to this article is available at http://dx.doi.org/10.1007/s00705-016-3160-9.

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Moeini, S., Saeidi, M., Fotouhi, F. et al. Synergistic effect of programmed cell death protein 1 blockade and secondary lymphoid tissue chemokine in the induction of anti-tumor immunity by a therapeutic cancer vaccine. Arch Virol 162, 333–346 (2017). https://doi.org/10.1007/s00705-016-3091-5

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