Identification of novel immunogenic human leukocyte antigen‐A2402‐binding epitopes of human papillomavirus type 16 E7 for immunotherapy against human cervical cancer

• Published in: Cancer Vol. 118; no. 8; pp. 2173 - 2183
• Main Authors: Jang, Sunphil, Kim, Young Tae, Chung, Hye Won, Lee, Kyoung‐Ryul, Lim, Jong‐Baeck, Lee, Kyungwon
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.04.2012; Wiley-Blackwell
• Subjects: Biological and medical sciences; cervical cancer; epitopes; Female genital diseases; Gynecology. Andrology. Obstetrics; HLA‐A24; HPV 16 E7; immunotherapy; Medical sciences; Tumors; Human; HPV 16 E7; HLA-System; Antigenic determinant; Leukocyte; Major histocompatibility system; V-Onc gene; HLA-A24; Papovaviridae; Malignant tumor; Female genital diseases; Papillomavirus; Virus; Antigen; Human papillomavirus 16; epitopes; Human papillomavirus; Cancerology; Treatment; Immunotherapy; Uterine cervix diseases; Cervical cancer; Cancer
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.26468

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, E761‐75(CDSTLRLCVQSTHVD) and E767‐81(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 E761‐75 and E767‐81 were synthesized. E761‐69(CDSTLRLCV) and E767‐76(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. E761‐69‐sensitized and E767‐76‐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 E767‐76‐sensitized PBMCs in vivo. CONCLUSIONS: E761‐69 and E767‐76 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. Peripheral blood mononuclear cells (PBMCs) and CD8+ cytotoxic T lymphocytes sensitized with newly identified human papillomavirus type 16 E761‐69 and E767‐76 epitopes for human leukocyte antigen‐A*2402 have cytolytic activity and antitumor effects against cervical cancer. Treatment with cisplatin followed by peptide‐sensitized PBMCs generates a more potent and long‐term antitumor effect than treatment with cisplatin alone.