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Identification of novel immunogenic human leukocyte antigen‐A*2402‐binding epitopes of human papillomavirus type 16 E7 for immunotherapy against human cervical cancer
Author(s) -
Jang Sunphil,
Kim Young Tae,
Chung Hye Won,
Lee KyoungRyul,
Lim JongBaeck,
Lee Kyungwon
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.26468
Subject(s) - epitope , peripheral blood mononuclear cell , cytotoxic t cell , cd8 , antigen , immunotherapy , cytotoxicity , in vivo , human leukocyte antigen , microbiology and biotechnology , in vitro , immunology , medicine , biology , immune system , biochemistry
BACKGROUND: A study was undertaken to identify new immunogenic human leukocyte antigen (HLA)‐A*2402‐restricted epitopes from human papillomavirus (HPV) type 16 E7 protein for immunotherapy against cervical cancer. METHODS: Synthetic overlapping peptides were screened by measuring the frequency of CD8 + cytotoxic T lymphocytes (CTLs) producing intracellular interferon‐γ (IFN‐γ) using flow cytometry and were validated in SiHa cells with a Cr release cytotoxicity assay. In vivo antitumor effects of peptide‐sensitized peripheral blood mononuclear cells (PBMCs) and isolated CD8 + CTLs were evaluated using BALB/c nude mice with SiHa cell xenotransplants. RESULTS: Among 14 overlapping 15‐amino acid peptides, E7 61‐75 (CDSTLRLCVQSTHVD) and E7 67‐81 (LCVQSTHVDIRTLED) induced significantly higher IFN‐γ production ( P < .05) and showed higher in vitro cytotoxicity against SiHa cells than did cells sensitized with the negative control. To determine the exact HLA‐A*2402‐restricted epitopes, a total of 25 overlapping 9‐ or 10‐amino acid peptides spanning E7 61‐75 and E7 67‐81 were synthesized. E7 61‐69 (CDSTLRLCV) and E7 67‐76 (LCVQSTHVDI) induced significantly greater IFN‐γ production as well as increased in vitro cytotoxicity against SiHa cells compared with those of other peptides and the negative control ( P < .01), and the antitumor effects of these peptide‐sensitized PBMCs were induced by CD8 + CTLs. E7 61‐69 ‐sensitized and E7 67‐76 ‐sensitized PBMCs and isolated CD8 + CTLs showed a much greater suppression of tumor growth in vivo compared with that of control groups treated with PBS ( P < .01). The authors also confirmed the synergistic antitumor effect of cisplatin followed by E7 67‐76 ‐sensitized PBMCs in vivo. CONCLUSIONS: E7 61‐69 and E7 67‐76 were identified as novel HPV type 16 E7 epitopes for HLA‐A*2402, which could be used for immunotherapy against cervical cancer. Cancer 2012. © 2011 American Cancer Society.