Tumor-associated antigen/IL-21-transduced dendritic cell vaccines enhance immunity and inhibit immunosuppressive cells in metastatic melanoma

Gene Ther. 2014 May;21(5):457-67. doi: 10.1038/gt.2014.12. Epub 2014 Feb 27.

Abstract

Dendritic cell (DC)-based vaccine approaches are being actively evaluated for developing immunotherapeutic agents against cancers. In this study, we investigated the use of engineered DCs expressing transgenic tumor-associated antigen hgp100 and the regulatory cytokine interleukin-21, namely DC-hgp100/mIL-21, as a therapeutic vaccine against melanoma. Tumor-bearing mice were injected intratumorally with transgenic DCs followed by three booster injections. Transgenic DC-hgp100/mIL-21 showed significant reduction in primary tumor growth and metastasis compared with DC-hgp100 alone and DC-mIL-21 alone. In vivo depletion of specific immune cell types (CD8(+) T, CD4(+) T and Natural killer (NK)-1.1(+) cells) effectively blocked the protective effect of this combinational vaccine. In adoptive transfer experiments, a survival rate of nearly 90% was observed at 60 days post-tumor inoculation for the combinational vaccine group. In contrast, all mice in the DC-hgp100 and DC-mIL-21-only groups died within 43-46 days after tumor challenge. Considerably increased levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte macrophage colony-stimulating factor (GM-CSF) and cytotoxic T lymphocytes (CTLs) were detected with the combination vaccine group compared with other individual treatment groups. In comparison with the DC-hgp100 or mIL-21 groups, the combinational DC-hgp100/mIL-21 vaccine also drastically suppressed the myeloid-derived suppressor cells (MDSCs) and T-regulatory (Treg) cell populations. Our findings suggest that a combinational DC- and gene-based hgp100 and mIL-21 vaccine therapy strategy warrants further evaluation as a clinically relevant cancer vaccine approach for human melanoma patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Cancer Vaccines / immunology*
  • Cell Proliferation
  • Cell- and Tissue-Based Therapy
  • Dendritic Cells / cytology
  • Dendritic Cells / transplantation*
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Interferon-gamma / biosynthesis
  • Interleukins / biosynthesis
  • Interleukins / genetics
  • Interleukins / immunology*
  • Killer Cells, Natural / immunology
  • Lymphocyte Depletion
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / mortality
  • Melanoma, Experimental / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / immunology
  • Survival Rate
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Vaccines, Synthetic / immunology

Substances

  • Antigens, Neoplasm
  • Cancer Vaccines
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • Vaccines, Synthetic
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • interleukin-21