Enhancement of antitumor effect by peptide vaccine therapy in combination with anti-CD4 antibody: Study in a murine model

https://doi.org/10.1016/j.bbrep.2016.02.010Get rights and content
Under a Creative Commons license
open access

Highlights

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

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

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

  • 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

Cited by (0)