Identification and characterization of survivin-derived H-2Kb-restricted CTL epitopes

Eur J Immunol. 2009 May;39(5):1419-24. doi: 10.1002/eji.200839098.

Abstract

Survivin is overexpressed in several malignancies and in tumor-associated endothelium making it an attractive target for therapeutic cytotoxic T-cell responses. Thus, it would be important to test this notion in preclinical models. Consequently, we screened the murine survivin sequence for potential binding K(b)-restricted octamer peptide epitopes. Two epitopes, which bind strongly to K(b), were selected to test their immunogenicity in vivo. Spleen cells from mice vaccinated by intradermal injection of mature DC pulsed with these peptides displayed reactivity to the respective epitopes. The natural processing and presentation of these epitopes by tumor cells was evident by the killing of murine melanoma cells by vaccination-induced T cells. Subcutaneous challenge with syngeneic melanoma demonstrated the protective immunity of this vaccination. Notably, analysis of the vessel density in subcutaneous tumors revealed that survivin-specific vaccination significantly reduced the number of intratumoral vessels. In summary, we demonstrated the immunogenicity of two K(b)-restricted peptide epitopes derived from the murine survivin protein; moreover, survivin-specific vaccination not only resulted in a reduction of tumor cells but also the tumor supplying blood vessels. The presented preclinical model for survivin-directed vaccination may serve as a valuable tool to improve already running clinical trials in a syngeneic tumor model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • H-2 Antigens / immunology*
  • Humans
  • Immunohistochemistry
  • Immunotherapy / methods
  • Inhibitor of Apoptosis Proteins
  • Melanoma / immunology
  • Melanoma / therapy
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / immunology*
  • Neovascularization, Pathologic / immunology
  • Repressor Proteins
  • Survivin
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Birc5 protein, mouse
  • Cancer Vaccines
  • Epitopes, T-Lymphocyte
  • H-2 Antigens
  • H-2Kb protein, mouse
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Repressor Proteins
  • Survivin