Analysis of cancer immune escape by epigenetic mechanism

• Project/Area Number: 18790250
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Human pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: HARIU Hiroyuki Sapporo Medical University, 医学部, 研究員 (40404587)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,610,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥210,000); Fiscal Year 2008: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
• Keywords: MHC class I / 乳癌 / 前立腺癌 / ピストン脱アセチル化 / DNAマイクロアレイ / ベータ2マイクログロブリン / HLA / 抗原提示 / ヒストン脱アセチル化 / 免疫逃避 / ウイルス感染症 / ヒストンアセチル化 / HLA class I / 癌抗原 / NHC class I / 遺伝子メチル化 / クロマチン免疫沈降法

Research Abstract

さまざまな正常組織と腫瘍組織におけるHLA class I関連分子の発現を検索し、ほとんどの癌種で約3割に発現低下があることを見出した。乳癌と前立腺癌では約8割にHLA発現消失または発現低下が認められた。乳癌と前立腺癌におけるHLA発現低下の分子機序を解析した結果、主にB2-microglobulin遺伝子のピストン脱アセチル化が原因であることが判明した。Geneticな変化や遺伝子メチル化の関与は低かった。ヒストン脱アセチル化機序による乳癌細胞の免疫逃避の解析を行い、HLA class I分子以外に、NK細胞標的分子、Immunodominantな癌抗原分子、Death受容体分子なども発現低下していることを見出した。ヒストン脱アセチル化阻害剤を作用させるとこれら分子の発現が回復した。ヒストン脱アセチル化阻害剤自体はT細胞機能に影響を及ぼさないことを証明し、癌免疫逃避を抑制する新たな免疫療法を提唱した。

Research Products

• [Journal Article] 腫瘍細胞におけるMHCクラスI表出のepigenetic機序による免疫回避 (2008)
  • Author(s): 井野田智子、鳥越俊彦
  • Journal Title: 臨床免疫・アレルギー科、特集1腫瘍の免疫回避機構と抗腫瘍免疫の誘導 50(4) Pages: 373-377
  • Peer Reviewed
• [Journal Article] HLA class I antigen expression is associated with a favorable prognosis in early Stage non-small Cell lung cancer (2007)
  • Author(s): Kikuchi E,Yamazaki K,Torigoe T,Cho Y,Miyamoto M,Oizumi S,Hommura F,Dosaka-Akita H and Nishimura M
  • Journal Title: Cancer Sci 98 Pages: 1424-1430
  • Peer Reviewed
• [Journal Article] Down-regulation of HLA class I antigen is an independent prognostic factor for clear cell renal cell carcinoma (2007)
  • Author(s): Kitamura H, Honma I,Torigoe T,Asanuma H, Sato N and Tsukamoto T
  • Journal Title: J Urol 177 Pages: 1269-1272
  • Peer Reviewed
• [Journal Article] Down-regulation of HLA class I antlgens in prostate cancer tissues and up-regulation by histone deacetylase inhibition (2007)
  • Author(s): Kitamura H, Torigoe T, Asanuma H, Honma I, Sato N, Tsukamoto T
  • Journal Title: J Urol 178 Pages: 692-696
  • Peer Reviewed
• [Journal Article] HLA class I antigen expression is associated with a favorable prognosis in early stage non-small cell lung cancer (2007)
  • Author(s): Kikuchi, E., et. al.
  • Journal Title: Cancer Sci 98 Pages: 1424-1430
  • Peer Reviewed
• [Journal Article] DoWn-regulation of HLA class I antigen is an independent prognostic factor for clearcell renalcell carcinolna (2007)
  • Author(s): Kitamura, H., et. al.
  • Journal Title: J Urol 177 Pages: 1269-1272
  • Peer Reviewed
• [Journal Article] DoWn-regulation of HLA class I antigens in proState cancer tissueS and up-regu1ati0n by hiStone deacety1ase inhibition (2007)
  • Author(s): Kitamura, H., et. al.
  • Journal Title: J Urol 178 Pages: 692-696
  • Peer Reviewed
• [Journal Article] Down-regulation of HLA class I antigen is an independent prognostic factor for clear cell renal cell carcinoma (2007)
  • Author(s): Kitamura H
  • Journal Title: J Urol 177 Pages: 1269-1272
• [Journal Article] Prognostic significance of HLA class I expression in osteosarcoma defined by anti-pan HLA class I monoclonal antibody, EMR8-5 (2006)
  • Author(s): Tsukahara T
  • Journal Title: Cancer Sci 97 Pages: 1374-1380
• [Journal Article] HLA-restricted specific tumor cytolysis by autologous T-lymphocytes infiltrating metastatic bone malignant fibrous histiocytoma of lymph node (2006)
  • Author(s): Tsukahara T
  • Journal Title: J Orthop Res 24 Pages: 94-101
• [Journal Article] Expression and antigenicity of survivin, an inhibitor of apoptosis family member, in bladder cancer : implications for specific immunotherapy (2006)
  • Author(s): Kitamura H
  • Journal Title: Urology 67 Pages: 955-959
• [Journal Article] Effect of human leukocyte antigen class I expression of tumor cells on outcome of intravesical instillation of bacillus calmette-guerin immunotherapy for bladder cancer (2006)
  • Author(s): Kitamura H
  • Journal Title: Clin Cancer Res 12 Pages: 4641-4644
• [Journal Article] Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma (2006)
  • Author(s): Komori H
  • Journal Title: Clin Cancer Res 12 Pages: 2689-2697
• [Presentation] Exploration of novel tumor antigens and translational study of peptide-based cancer vaccine-from bench to bedside and lesson from bedside (2008)
  • Author(s): Torigoe, T., et.al.
  • Organizer: ISOBM2008
  • Place of Presentation: 東京
  • Year and Date: 2008-10-06
• [Presentation] Impact of HLA class I down-regulation in the immune escape of cancer and its prevention by histone deacetylase inhibitors (2007)
  • Author(s): Torigoe, T., Asanuma, H., Hirohashi, Y., Iwayama, Y., Toyoda, N., Honma, I., Kitamura, H., Tsukamoto, T., Hirata, K. and Sato, N.
  • Organizer: 12th World Congress on Advances in Oncology and 10th International Symposium on Molecular Medicine
  • Place of Presentation: Crete, Greece
• [Presentation] Epigenetic mechanism of cancer immune escape and its regulation by histone deacetylase inhibitors (2007)
  • Author(s): Torigoe T, Asanuma H, Sato N
  • Organizer: 日本癌学会 International Session
  • Place of Presentation: 横浜
• [Book] 癌免疫監視機構のエスケープ機序としてのHLAクラスIの発現低下、ハイパーサーミック・イムノロジー (2008)
  • Author(s): 平田公一、九冨五郎、奥谷浩一、豊田宣彦、岩山祐司、亀嶋秀和、鶴間哲弘、古畑智久、鳥越俊彦、佐藤昇志
  • Publisher: 診断と治療社
• [Book] エピジェネティクスにより制御される腫瘍の免疫逃避機構、Annual Review免疫2008 (2008)
  • Author(s): 中津川宗秀、鳥越俊彦
  • Publisher: 中外医学社
• [Patent(Industrial Property Rights)] がん幹細胞分子マーカー (2008)
  • Inventor(s): 鳥越俊彦, 廣橋良彦、高橋あかり、佐藤昇志
  • Industrial Property Rights Holder: 札幌医大JST
  • Industrial Property Number: 2008-275539
  • Filing Date: 2008-10-27
• [Patent(Industrial Property Rights)] POTENTIATION OF CELLULAR IMMUNITY USING HISTONE DESCETYLASE (HDAC) INHIBITORS (2007)
  • Inventor(s): 鳥越俊彦、佐藤昇志、淺沼広子、藤井暢弘、石埜正穂
  • Industrial Property Rights Holder: 科学技術振興機構、札幌医大
  • Filing Date: 2007-12-06
  • Overseas
• [Patent(Industrial Property Rights)] ヒストン脱アセナル化酵素阻害剤を用いた癌免疫および感染免疫の増強法 (2006)
  • Inventor(s): 鳥越 俊彦, 佐藤 昇志 他2名
  • Industrial Property Rights Holder: JST,北海道
  • Industrial Property Number: 2006-281928
  • Filing Date: 2006-09-15