Dendritic cell therapy with interferon-alpha synergistically suppresses outgrowth of established tumors in a murine colorectal cancer model

Gene Ther. 2006 Jan;13(1):78-87. doi: 10.1038/sj.gt.3302608.

Abstract

Both dendritic cell (DC)-based immunotherapy and interferon (IFN)-alpha therapy have been proved to have potent long-lasting antitumor effects. In anticipation of synergistic antitumor effects, we performed combination therapy with DCs and IFN-alpha gene-transduced murine colorectal cancer MC38 cells (MC38-IFN-alpha). DCs incubated with MC38-IFN-alpha, but not neomycin-resistance gene-transduced MC38 cells (MC38-Neo), effectively enhanced proliferation of allogeneic splenocytes in vitro. In 12 of 17 mice, DCs in combination with MC38-IFN-alpha prevented the development of a parental tumor, while DCs and MC38-Neo did in only three of 17 mice (P=0.008). In a therapeutic model of an established parental tumor, inoculation of DCs and MC38-IFN-alpha suppressed the growth of the established parental tumors significantly compared with the administration of DCs with MC38-Neo or naive splenocytes with MC38-IFN-alpha (P=0.016 and 0.024, respectively). Analyses of immunohistochemistry and tumor-infiltrating mononuclear cells showed that CD8(+), CD11c(+), and NK1.1(+) cells markedly infiltrated the established tumors of mice treated with DCs and MC38-IFN-alpha. From the results of observation of parental tumor outgrowth in immune cell-depleted mice, CD8(+) cells, and asialo-GM-1(+) cells were thought to contribute to the antitumor effects induced by the combination therapy. Furthermore, MC38-specific cytolysis was detected when splenocytes of mice inoculated with DCs and MC38-IFN-alpha cells were stimulated with MC38-IFN-alpha cells in vitro. Since DC-based immunotherapy in combination with IFN-alpha-expressing tumor cells induces potent antitumor cellular immune responses, it should be considered for clinical application.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer / methods*
  • Animals
  • Cell Line, Tumor
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / therapy*
  • Dendritic Cells / immunology*
  • Female
  • Genetic Therapy / methods*
  • Genetic Vectors / pharmacology
  • Interferon-gamma / genetics*
  • Interferon-gamma / immunology
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Retroviridae / genetics
  • T-Lymphocytes, Cytotoxic / immunology
  • Transduction, Genetic / methods

Substances

  • Interferon-gamma