Mechanisms of escape from trastuzumab-mediated ADCC in esophageal squamous cell carcinoma.

2011 Fiscal Year Final Research Report

• Project/Area Number: 22791268
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: University of Yamanashi
• Principal Investigator: KAWAGUCHI Yoshihiko 山梨大学, 大学院・医学工学総合研究部, 助教 (80402048)
• Project Period (FY): 2010 – 2011
• Keywords: 食道扁平上皮癌 / 抗体療法 / trastuzumab / Herceptin / 細胞障害活性

Research Abstract

We elucidated the mechanisms of escape from Trastuzumab-mediated ADCC using esophageal squamous cell carcinoma cell clones. Esophageal SCC cell line TE4, which is highly susceptible to Trastuzumab-mediated ADCC, were repeatedly treated with Trastuzumab-mediated ADCC, and the surviving tumor cells are cloned by limited dilution and selected as 68 escaped tumor clones. Furthermore, the degree of permeabilization induced by PFN and apoptosis induced by the combination of PFN with GrB in tumor cell clones was analyzed. As a result, lower sensitivity for PFN/GrB on tumor clones was related to the reduced Trastuzumab-mediated ADCC. In conclusion, lower susceptibility to the perforin-granzyme system is one of the important mechanisms explaining escape from Trastuzumab-mediated ADCC.

Research Products

• [Journal Article] Lapatinib enhances Hercep tin-mediated antibody-dependent cellu lar cytotoxicity by up-regulation of cell surface HER2 expression (2011)
  • Author(s): Maruyama T, Mimura K, Izawa S, InoueA, Shiba S, Watanabe M, Kawaguchi Y, Inoue M, Nogata H, Inoue S, Fujii H, and Kono K
  • Journal Title: Anticancer Res Volume: 31(9) Pages: 2999-3005
  • Peer Reviewed
• [Journal Article] Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody dependent cellular cytotoxicity(ADCC) of EGFR and HER2 over-expressing esophageal cancer cell lines (2011)
  • Author(s): Mimura K, Kono K, Maruyama T, WatanabeM, Izawa S, Shiba S, Mizukami Y, Kawaguchi Y, Inoue M, Kono T, Choudhury A, Kiessking R, and Fujii H
  • Journal Title: Int J Cancer Volume: 29(10) Pages: 2408-2416
  • Peer Reviewed
• [Journal Article] Inverse correlation of HER2 with MHC class I expression on oesophageal squamous cell carcinoma (2010)
  • Author(s): Maruyama T, Mimura K, Sato E, Watanabe M, Mizukami Y, Kawaguchi Y, Ando T, Kinouchi H, Fujii H, and Kono K
  • Journal Title: Br J Cancer Volume: 103巻 Pages: 552-9
  • Peer Reviewed
• [Journal Article] Interleukin-21 can efficiently restore impaired antibody-dependent cell-mediated cytotoxicity in patients with oesophageal squamous cell carcinoma (2010)
  • Author(s): Watanabe M, Kono K, Kawaguchi Y, Mizukami Y, Mimura K, Maruyama T, Fujii H
  • Journal Title: Br J Cancer Volume: 102巻 Pages: 520-9
  • Peer Reviewed
• [Presentation] 食道扁平上皮癌患者におけるNK細胞機能不全とその回避方法について (2011)
  • Author(s): 三村耕作, 他
  • Organizer: 第66回日本消化器外科学会総会
  • Place of Presentation: 愛知県
  • Year and Date: 2011-07-13
• [Presentation] HER-1(EGFR), HER-2を分子標的とした食道扁平上皮癌に対する新規治療-外科治療に対する有効な補助療法- (2011)
  • Author(s): 河野浩二, 他
  • Organizer: 第66回日本消化器外科学会総会
  • Place of Presentation: 愛知県
  • Year and Date: 2011-07-13
• [Presentation] 食道癌に対する免疫療法の新規開発-HER family分子標的治療とペプチドワクチン (2011)
  • Author(s): 三村耕作, 他
  • Organizer: 第36回日本外科系連合学会学術集会
  • Place of Presentation: 千葉県
  • Year and Date: 2011-06-16
• [Presentation] 食道扁平上皮癌におけるHER2を標的とした分子標的治療と免疫治療について (2011)
  • Author(s): 三村耕作, 他
  • Organizer: 第32回癌免疫外科研究会
  • Place of Presentation: 和歌山県
  • Year and Date: 2011-05-19