An attempt to identify new antigens recognized by tumor-specific cytotoxic T lymphocytes using a HLA-modified ovarian cancer cell line as an artificial antigen presenting cell

• Project/Area Number: 24659727
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Nagoya University
• Principal Investigator: KIKKAWA Fumitaka 名古屋大学, 医学(系)研究科(研究院), 教授 (40224985)
• Co-Investigator(Kenkyū-buntansha): SUZUKI Shiro 名古屋大学, 医学部附属病院, 助教 (20612758) ; SHIBATA Kiyosumi 名古屋大学, 医学系研究科, 准教授 (90335026)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 卵巣癌 / 腫瘍免疫療法 / 腫瘍免疫

Outline of Final Research Achievements

We built a novel method for inducing cancer-reactive cytotoxic T lymphocytes (CTLs) restricted to an HLA allele of interest. We used an artificial antigen presenting cell (aAPC), TOV21G that express a single HLA-A*24:02 allele and was originally derived from an ovarian clear cell carcinoma. Several CTL clones were established using aAPC stimulation. Then, cDNA library construction using mRNA extracted from the parental TOV21G cells and subsequent expression cloning was conducted.
These experiments revealed that a CTL clone recognized a minimal epitope peptide RYEFGQALF, which was derived from an autoantigen claudin-1 presented by HLA-A24:02 molecules.
Another clone responded not only to ovarian cancer cells in the context of HLA-A*24:02 but also to allogeneic HLA-Cw*07:02 molecules through cross-reactive TCR recognition. Expression screening using a cDNA library revealed that this alloreactivity was mediated through the 9-mer peptide VRTPYTMSY, derived from RNA-binding motif protein 4.

Research Products

• [Journal Article] Oncologic outcome after recurrence in patients with stage I epithelial ovarian cancer: are clear-cell and mucinous histological types a different entities? (2014)
  • Author(s): Kajiyama H, Mizuno M, Shibata K, Umezu T, Suzuki S, Yamamoto E, Mitsui H, Sekiya R, Niimi K, Kawai M, Nagasaka T, Kikkawa F.
  • Journal Title: Eur J Obstet Gynecol Reprod Biol. Volume: 181 Pages: 305-310
  • Peer Reviewed
• [Journal Article] GPC3 expression in mouse ovarian cancer induces GPC-specific T cell-mediated immune response through M1 macrophages and suppresses tumor growth. (2014)
  • Author(s): Luo C, Shibata K, Suzuki S, Kajiyama H, Senga T, Koya Y, Daimon M, Yamashita M, Kikkawa F.
  • Journal Title: Oncol Rep. Volume: 32 Issue: 3 Pages: 913-21
  • DOI: 10.3892/or.2014.3300
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathologic features of epithelial ovarian carcinoma in younger vs. older patients: analysis in Japanese women. (2014)
  • Author(s): Yoshikawa N, Kajiyama H, Mizuno M, Shibata K, Kawai M, Nagasaka T, Kikkawa F.
  • Journal Title: J Gynecol Oncol. Volume: 25(2) Pages: 118-123
  • Peer Reviewed / Open Access
• [Journal Article] Possible association between stem-like hallmark and radioresistance in human cervical carcinoma cells. (2014)
  • Author(s): Kumazawa S, Kajiyama H, Umezu T, Mizuno M, Suzuki S, Yamamoto E, Mitsui H, Sekiya R, Shibata K, Kikkawa F.
  • Journal Title: J Obstet Gynaecol Res. Volume: 40(5) Pages: 1389-1398
  • Peer Reviewed
• [Journal Article] PLAGL2 regulates actin cytoskeletal architecture and cell migration. (2014)
  • Author(s): Sekiya R, Maeda M, Yuan H, Asano E, Hyodo T, Hasegawa H, Ito S, Shibata K, Hamaguchi M, Kikkawa F, Kajiyama H, Senga T.
  • Journal Title: Carcinogenesis Volume: 35 Issue: 9 Pages: 1993-2001
  • DOI: 10.1093/carcin/bgu081
  • Peer Reviewed
• [Journal Article] An HLA-modified ovarian cancer cell line induced CTL responses specific to an epitope derived from claudin-1 presented by HLA-A*24:02 molecules (2013)
  • Author(s): Kondo S, Demachi-Okamura A, Hirosawa T, Maki H, Fujita M, Uemura Y, Akatsuka Y, Yamamoto E, Shibata K, Ino K, Kikkawa F, Kuzushima K.
  • Journal Title: Hum Immunol Volume: 74 Issue: 9 Pages: 1103-1110
  • DOI: 10.1016/j.humimm.2013.06.030
  • Peer Reviewed
• [Journal Article] Significant clinical response of progressive recurrent ovarian clear cell carcinoma to glypican-3-derived peptide vaccine therapy: Two case reports. (2013)
  • Author(s): Suzuki S, Shibata K, Kikkawa F, Nakatsura T
  • Journal Title: Hum Vaccin Immunother Volume: 19;10(2) Issue: 2 Pages: 338-343
  • DOI: 10.4161/hv.27217
  • Peer Reviewed
• [Journal Article] ALX1 induces snail expression to promote epithelial-to-mesenchymal transition and invasion of ovarian cancer cells. (2013)
  • Author(s): Yuan H, Kajiyama H, Ito S, Yoshikawa N, Hyodo, Shibata K,Hamaguch M, Kikkawa F, Senga T.
  • Journal Title: Cancer Res Volume: 73(5) Issue: 5 Pages: 1581-1590
  • DOI: 10.1158/0008-5472.can-12-2377
  • Peer Reviewed
• [Presentation] CLINICAL AND IMMUNOLOGICAL ANALYSIS IN CLINICAL STUDY OF GLYPICAN-3 PEPTIDE VACCINE FOR PATIENTS WITH OVARIAN CLEAR CELL CARCINOMA IN FIRST CLINICAL REMISSION (2014)
  • Author(s): 鈴木史朗, 三井寛子, 関谷龍一郎, 水野美香, 梶山広明, 柴田清住, 吉川史隆
  • Organizer: The 15th Biennial Meeting of the International Gynecologic Cancer Society (IGCS 2014)
  • Place of Presentation: Melbourne（Australia）
  • Year and Date: 2014-11-08 – 2014-11-11
• [Presentation] 卵巣明細胞腺癌に対する寛解維持Glypican-3 ペプチドワクチン療法の検討 (2014)
  • Author(s): 鈴木史朗, 柴田清住, 三井寛子, 関谷龍一郎, 水野美香, 梶山広明, 吉川史隆, 中面哲也
  • Organizer: 第56回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 栃木県総合文化センター(栃木県宇都宮市）
  • Year and Date: 2014-07-17 – 2014-07-19
• [Presentation] 臨床的寛解が得られた卵巣明細胞腺癌に対するGlypican-3ペプチドワクチン療法の臨床的・免疫学的検討 (2014)
  • Author(s): 鈴木史朗, 柴田清住, 関谷龍一郎, 三井 寛子, 梅津朋和, 水野美香, 梶山広明, 吉川史隆
  • Organizer: 第66回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区）
  • Year and Date: 2014-04-18 – 2014-04-20
• [Presentation] ワークショップ2：卵巣明細胞腺癌の予後改善を目指して 進行卵巣明細胞腺癌に対するGlypican3 ペプチドワクチン療法 ～抗腫瘍効果が得られた2 例を中心に～ (2013)
  • Author(s): 鈴木史朗、柴田清住、梅津朋和、水野美香、梶山広明、吉川史隆、中面哲也
  • Organizer: 第54回 日本婦人科腫瘍学会学術講演会
  • Place of Presentation: ホテル グランパシフィック LE DAIBA(東京都港区)
• [Presentation] Glypican-3-derived Peptide Vaccine Therapy combined with Chemotherapy against Progressive Ovarian Clear Cell Carcinoma (2013)
  • Author(s): 鈴木史朗、柴田清住、吉川史隆、中面哲也
  • Organizer: 1st International Symposium on Immunotherapy
  • Place of Presentation: London, England
• [Presentation] Glypican-3 could be an effective target for immunotherapy combined with chemotherapy against ovarian clear cell carcinoma. (2012)
  • Author(s): 鈴木史朗、芳川修久、水野美香、梶山広明、柴田清住、中面哲也、吉川史隆
  • Organizer: XX FIGO World Congress of Gynecology and Obstetrics
  • Place of Presentation: Rome
• [Presentation] Immune monitoring in clinical study of GPC3 peptide vaccine for patients with ovarian clear cell carcinoma (卵巣明細胞腺癌に対するGPC3ペプチドワクチン療法における免疫モニタリングおよびGPC3ペプチド特異的CTLの誘導) (2012)
  • Author(s): 鈴木史朗、柴田清住、吉川聡明、中面哲也、吉川史隆
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ﾛｲﾄﾝ札幌、さっぽろ芸文館、札幌市教育文化会館 札幌市