Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family, Livin/ML-IAP in lung cancer.
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.
Hariu
Hiroyuki
H
Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17 Chuo-ku, Sapporo 060-8556, Japan.
Hirohashi
Yoshihiko
Y
Torigoe
Toshihiko
T
Asanuma
Hiroko
H
Hariu
Midori
M
Tamura
Yasuaki
Y
Aketa
Katsuyuki
K
Nabeta
Chika
C
Nakanishi
Katsuya
K
Kamiguchi
Kenjiro
K
Mano
Yoshinori
Y
Kitamura
Hiroshi
H
Kobayashi
Junichi
J
Tsukahara
Tomohide
T
Shijubo
Noriharu
N
Sato
Noriyuki
N
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism; D059871:HLA-A24 Antigen; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D051034:Inhibitor of Apoptosis Proteins; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D012313:RNA