Enhancement of antitumor effect by peptide vaccine ...

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Highlights

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  Peptide-specific CTL induction and function were enhanced by depletion of CD4+ cells.

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  Anti-tumor effect by the peptide vaccine was enhanced by the depletion of CD4+ cells.

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  Metastasis was inhibited by vaccine with depletion of CD4+ cells in a murine model.

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  Combination with the depletion of CD4+ cells could be a new cancer vaccine strategy.

Abstract

Purpose

The clinical efficacy of cancer peptide vaccine therapy is insufficient. To enhance the anti-tumor effect of peptide vaccine therapy, we combined this therapy with an anti-CD4 mAb (GK1.5), which is known to deplete CD4+ cells, including regulatory T cells (Tregs).

Methods

To determine the treatment schedule, the number of lymphocyte subsets in the peripheral blood of mice was traced by flow cytometry after administration of anti-CD4 mAb. The ovalbumin (OVA)257–264 peptide vaccine was injected intradermally and anti-CD4 mAb was administered intraperitoneally into C57BL/6 mice at different schedules. We evaluated the enhancement of OVA peptide-specific cytotoxic T lymphocyte (CTL) induction in the combination therapy using the ELISPOT assay, CD107a assay, and cytokine assay. We then examined the in vivo metastasis inhibitory effect by OVA peptide vaccine therapy in combination with anti-CD4 mAb against OVA-expressing thymoma (EG7) in a murine liver metastatic model.

Results

We showed that peptide-specific CTL induction was enhanced by the peptide vaccine in combination with anti-CD4 mAb and that the optimized treatment schedule had the strongest induction effect of peptide-specific CTLs using an IFN-γ ELISPOT assay. We also confirmed that the CD107a+ cells secreted perforin and granzyme B and the amount of IL-2 and TNF produced by these CTLs increased when the peptide vaccine was combined with anti-CD4 mAb. Furthermore, metastasis was inhibited by peptide vaccines in combination with anti-CD4 mAb compared to peptide vaccine alone in a murine liver metastatic model.

Conclusion

The use of anti-CD4 mAb in combination with the OVA peptide vaccine therapy increased the number of peptide-specific CTLs and showed a higher therapeutic effect against OVA-expressing tumors. The combination with anti-CD4 mAb may provide a new cancer vaccine strategy.

Abbreviations

QOL

quality of life

GPC3

glypican-3

CTL

cytotoxic T lymphocyte

HCC

hepatocellular carcinoma

PD-1

programmed death-1

Treg

regulatory T cell

mAb

monoclonal antibody

TGF-β

transforming growth factor-βl

DC

dendritic cell

OVA

ovalbumin

IFN-γ

interferon-γ

ELISPOT assay

enzyme-linked immunospot assay

MHC

major histocompatibility complex

FITC

fluorescein isothiocyanate

PE

phycoerythrin

FOXP3

forkhead box P3

7-AAD

7-amino-actinomycin D

IL-2

interleukine-2

TNF

tumor necrosis factor

Keywords

Cancer

Immunotherapy

Peptide vaccine

Anti-CD4 antibody

Murine liver metastatic model

Copyright © 2016 The Authors. Published by Elsevier B.V.