Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family, Livin/ML-IAP in lung cancer

Clin Cancer Res. 2005 Feb 1;11(3):1000-9.

Abstract

CD8(+) CTLs have an essential role in immune response against tumor. Although an increasing number of tumor-associated antigens that can be recognized by CTLs have been identified from human tumors, a limited number of tumor-associated antigens is known in lung cancer. In addition, because some of them are expressed in noncancerous tissues, there exist limitations in their application to tumor immunotherapy. Livin/ML-IAP is one of recently identified inhibitor of apoptosis protein (IAP) family, which is overexpressed in melanoma cells. In this report, we show that Livin/ML-IAP is aberrantly expressed in many lung cancer cell lines and primary lung cancer tissues, whereas it is not detectable in normal tissues, including lung by reverse transcription-PCR methods. To identify HLA-A24-restricted T-cell epitopes of Livin/ML-IAP, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. It was revealed that Livin7 peptide (amino acid sequence, KWFPSCQFLL) had the highest affinity to HLA-A24. By stimulating peripheral blood lymphocytes of HLA-A24-positive lung cancer patients with Livin7 peptide in vitro, the peptide-specific CTLs were successfully induced from four of five patients with Livin/ML-IAP-positive lung cancer but not from any of four patients without Livin/ML-IAP expression in their cancer tissues. Furthermore, the CTLs induced by Livin7 peptide showed cytotoxicity against Livin/ML-IAP(+) lung cancer cell lines in an HLA-A24-restricted manner. Our data suggest that Livin/ML-IAP may be an excellent target antigen in immunotherapy for lung cancer and Livin7 peptide may serve as a potent peptide vaccine for HLA-A*2402(+)/Livin(+) lung cancer patients.

Publication types

  • Comparative Study

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Amino Acid Sequence
  • Binding, Competitive
  • Cell Line, Tumor
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • HLA-A Antigens / immunology
  • HLA-A Antigens / metabolism
  • HLA-A24 Antigen
  • Humans
  • Immunohistochemistry
  • Immunotherapy
  • Inhibitor of Apoptosis Proteins
  • K562 Cells
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / immunology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Male
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • Neoplasm Proteins / metabolism
  • RNA / genetics
  • RNA / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • BIRC7 protein, human
  • Epitopes, T-Lymphocyte
  • HLA-A Antigens
  • HLA-A24 Antigen
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins
  • RNA