Identification of an HLA-A24-restricted cytotoxic T lymphocyte epitope from human papillomavirus type-16 E6: the combined effects of bortezomib and interferon-gamma on the presentation of a cryptic epitope.
About 50% of cervical cancers are associated with human papillomavirus type 16 (HPV-16), and since the HPV-16 E6 and E7 oncoproteins are constitutively expressed in the tumor cells, they are attractive targets for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. Nevertheless, only a limited number of HPV-16 E6 epitopes have been identified to date. Using reverse immunological methods, we have generated a CTL clone against the HPV-16 E6(49-57) epitope restricted by HLA-A*2402, which is the most common allele in Japan and relatively frequent worldwide, capable of lysing 293T cells transduced with HLA-A*2402 and HPV-16 E6. Although it was unable to recognize the SiHa cervical cancer cell line positive for HPV-16 and HLA-A*2402, the cells became susceptible to lysis when transduced with E6-E7 genes, which was unexpectedly offset by pretreatment with interferon (IFN)-gamma alone. Interestingly, however, combined pretreatment with a proteasome inhibitor, bortezomib and IFN-gamma fully restored CTL-mediated lysis of the original SiHa cells. Furthermore, such intervention of 2 of 4 other cervical cancer cell lines expressing HPV-16 E6 and HLA-A*2402 was found to induce IFN-gamma production by specific CTLs. Tetramer analysis further revealed that induction of E6(49-57)-specific T cells was possible in 5 of 7 patients with HPV-16-positive high grade cervical intraepithelial neoplasia or cervical cancer by in vitro stimulation with E6(49-57) peptide. Thus, these findings together indicate that E6(49-57) is a candidate epitope for immunotherapy and immunological monitoring of such patients.
Morishima
Satoko
S
Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Akatsuka
Yoshiki
Y
Nawa
Akihiro
A
Kondo
Eisei
E
Kiyono
Tohru
T
Torikai
Hiroki
H
Nakanishi
Toru
T
Ito
Yoshinori
Y
Tsujimura
Kunio
K
Iwata
Kosuke
K
Ito
Koji
K
Kodera
Yoshihisa
Y
Morishima
Yasuo
Y
Kuzushima
Kiyotaka
K
Takahashi
Toshitada
T
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D059871:HLA-A24 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000473:pathology / Q000821:virology
D001897:Boronic Acids; C068651:E6 protein, Human papillomavirus type 16; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D009856:Oncogene Proteins, Viral; D011480:Protease Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D012097:Repressor Proteins; D000069286:Bortezomib; D007371:Interferon-gamma