Human IP10-scFv and DC-induced CTL synergistically inhibit the growth of glioma in a xenograft model

Tumour Biol. 2014 Aug;35(8):7781-91. doi: 10.1007/s13277-014-1867-3. Epub 2014 May 10.

Abstract

The epidermal growth factor receptor (EGFR) mutant of EGFRvIII is highly expressed in glioma cells, and the EGFRvIII-specific dendritic cell (DC)-induced tumor antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) may hold promise in cancer immunotherapy. Interferon (IFN)-γ-inducible protein (IP)-10 (IP-10) is a potent inhibitor of angiogenesis and can recruit CXCR3(+) T cells, including CD8(+) T cells, which are important for the control of tumor growth. In this study, we assessed if the combination of IP10-EGFRvIIIscFv with DC-induced CTLs would improve the therapeutic antitumor efficacy. IP10-scFv was generated by linking the human IP-10 gene with the DNA fragment for anti-EGFRvIIIscFv with a (Gly4Ser)3 flexible linker, purified by affinity chromatography, and characterized for its anti-EGFRvIII immunoreactivity and chemotactic activity. DCs were isolated from human peripheral blood monocyte cells and pulsed with EGFRvIII-peptide, then co-cultured with autologous CD8(+) T cells. BALB/c-nu mice were inoculated with human glioma U87-EGFRvIII cells in the brain and treated intracranially with IP10-scFv and/or intravenously with DC-induced CTLs for evaluating the therapeutic effect. Treatment with both IP10-scFv and EGFRvIII peptide-pulsed, DC-induced CTL synergistically inhibited the growth of glioma and prolonged the survival of tumor-bearing mice, which was accompanied by the inhibition of tumor angiogenesis and enhancement of cytotoxicity, thereby increasing the numbers of brain-infiltrating lymphocytes (BILs) and prolonging the residence time of CTLs in the tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / pathology
  • Brain Neoplasms / therapy*
  • Cell Line, Tumor
  • Chemokine CXCL10 / genetics*
  • Dendritic Cells / immunology*
  • ErbB Receptors / metabolism
  • Female
  • Glioma / pathology
  • Glioma / therapy*
  • HEK293 Cells
  • Humans
  • Immunotherapy, Adoptive
  • Mice
  • Mice, Inbred BALB C
  • NIH 3T3 Cells
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / therapeutic use*
  • Single-Chain Antibodies / genetics*
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • CXCL10 protein, human
  • Chemokine CXCL10
  • Recombinant Fusion Proteins
  • Single-Chain Antibodies
  • ErbB Receptors