Identification of tumor-associated antigen in malignant pleural mesothelioma for establishment of tumor specific immunotherapy.

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591829
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Thoracic surgery
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: SOU Tetuya 産業医科大学, 医学部, 非常勤医師 (90412642)
• Co-Investigator(Kenkyū-buntansha): HANAGIRI Takeshi 産業医科大学, 医学部, 准教授 (30299614) ; TAKENOYAMA Mituhiro 産業医科大学, 医学部, 非常勤講師 (10309966) ; BABA Teturou 産業医科大学, 医学部, 助教 (10506348)
• Project Period (FY): 2009 – 2011
• Keywords: 悪性胸膜中皮腫 / 細胞障害性T細胞 / 腫瘍浸潤リンパ球 / SEREX法 / Thrombosposqoudin 2 / 腫瘍マーカー / 腫瘍免疫

Research Abstract

Malignant pleural mesothelioma(MPM) is difficult to diagnose at an early stage. The present study attempted to identify tumor-associated antigen, which is applicable for surrogate biomarkers of diagnosis or for antigen-targeted therapy for MPM.
Bulk cytotoxic T lymphocytes(CTL) were induced successfully by co-culture of lymphocytes and the autologous MPM cell line L324MSO. Then, CTL clone was established by the limiting dilution method. CTL clone showed cytotoxic activity against L324MSO, but not autologous PHA blast or K562 in an HLA-restricted manner. Using the CTL clone, an antigen-coding gene has been screened using the cDNA expression cloning technique.
On the other hand, tumor-associated antigens were also identified by using antibody derived from tumor-infiltrating B lymphocytes in MPM. Immunoscreening of the cDNA libraries was carried out by serological identification of antigens by a recombinant expression cloning method(SEREX), and 2 antigens were identified as MPM-associated antigens(Gene-X and thrombospondin-2(THBS-2)). Antibodies against Gene-X and THBS-2 in the sera were measured by ELISA method. A total of 124 sera were investigated ; 97 patients were finally diagnosed with MPM and 27 were diagnosed as non-malignant diseases(NM). The serum antibody-titer against THBS-2 was significantly higher in MPM patients than in NM(P<0.01), but there was no difference in the serum antibody-titer against Gene-X. The serum antibody-titer against THBS-2 was a useful non-invasive marker in the diagnosis of MPM. Furthermore, the suppression of Gene-X and THBS-2 expression by transfection with small interfering RNA resulted in suppression of the cell cycle associated gene and apoptosis associated gene, and the growth inhibition of MPM cell lines. These results may indicate that Gene-X and THBS-2 are may be a useful candidate as a target for specific immunotherapy.

Research Products

• [Journal Article] Identification of a tumour associated antigen in lung cancer patients with asbestos exposure (2010)
  • Author(s): Yasuda M, Hanagiri T, Shigematsu Y, Onitsuka T, Kuroda K, Baba T, Mizukami M, Ichiki Y, Uramoto H, Takenoyama M, Yasumoto K
  • Journal Title: Anticancer Res Volume: 30 Pages: 2631-2639
  • Peer Reviewed
• [Journal Article] 悪性胸膜中皮腫の治療経験 (2010)
  • Author(s): 浦本秀隆, 下川秀彦, 馬場哲郎, 重松義紀, 永田好香, 小野憲司, 竹之山光広, 花桐武志
  • Journal Title: J UOEH Volume: 32 Pages: 257-264
  • Peer Reviewed
• [Journal Article] Tumor antigens and serological biomarkers for the diagnosis of asbestos-related malignancies (2010)
  • Author(s): Yasuda M, Hanagiri T, Takenoyama M, Yasumoto K
  • Journal Title: Curr Res in Cancer Volume: 4 Pages: 39-40
  • Peer Reviewed
• [Journal Article] TS, DHFR and GARFT Expression in Non-squamous Cell Carcinoma of NSCLC and Malignant Pleural Mesothelioma Patients Treated with Pemetrexed (2010)
  • Author(s): Uramoto H, Onitsuka T, Shimokawa H, Hanagiri T
  • Journal Title: Anticancer Res Volume: 30 Pages: 4309-4316
  • Peer Reviewed
• [Journal Article] Malignant mesothelioma-associated antigens recognized by tumor-infiltrating B cells and the clinical significance of the antibodytiters (2009)
  • Author(s): Shigematsu Y, Hanagiri T, Kuroda K, Baba T, Mizukami M, Ichiki Y, Yasuda M, Takenoyama M, Sugio K, Yasumoto K
  • Journal Title: Cancer Sci Volume: 100 Pages: 1326-1334
  • DOI: DOI:10.1111/j.1349-7006.2009.01181.x
  • Peer Reviewed
• [Journal Article] 選択的ワクチン療法:非特異的免疫療法からの脱出:現状と展望MAGE抗原を用いた免疫療法の可能性 (2009)
  • Author(s): 花桐武志, 杉尾賢二, 安元公正
  • Journal Title: Oncology Volume: 6 Pages: 72-80
  • Peer Reviewed
• [Journal Article] Results of Surgical Treatment for Patients with Small Cell Lung Cancer (2009)
  • Author(s): Hanagiri T, Sugio K, Baba T, Ichiki Y, Yasuda M, Uramoto H, Ohga T, Takenoyama M, Yasumoto K
  • Journal Title: J Thorac Oncol Volume: 4 Pages: 964-968
  • Peer Reviewed
• [Journal Article] Congenital tracheoesophageal fistula in an elderly patient withthoracic empyema (2009)
  • Author(s): Yasuda M, Hanagiri T, Ichiki Y, Takenoyama M, Sugio K, Yasumoto K
  • Journal Title: Gen Thorac Cardiovasc Surg Volume: 57 Pages: 622-624
  • DOI: DOI:10.1007/s11748-009-0450-0
  • Peer Reviewed
• [Presentation] 新規悪性胸膜中皮腫関連抗原の機能解析と腫瘍マーカーとしての意義 (2011)
  • Author(s): 重松義紀, 黒田耕志, 馬場哲郎, 竹中賢, 近石泰弘, 岡壮一, 中川誠, 下川秀彦, 浦本秀隆, 宗知子, 花桐武志, 田中文啓
  • Organizer: 第52回日本肺癌学会総会
  • Place of Presentation: 大阪国際会議場大阪
  • Year and Date: 20111103-04
• [Presentation] 悪性胸膜中皮腫に対する腫瘍特異的免疫応答の解析(第2報) (2011)
  • Author(s): 竹之山光広, 重松義紀, 馬場哲郎, 永田好香, 浦本秀隆, 宗知子, 花桐武志, 田中文啓
  • Organizer: 第29回産業医科大学学会総会
  • Place of Presentation: 産業医科大学ラマツィーホール北九州
  • Year and Date: 2011-10-18
• [Presentation] Diagnostic markers for malignatn pleural mesothelinoma : Serum antibody against antigens recognized by antibodies produced from tumor infiltraring B cells (2010)
  • Author(s): Shigematsu Y, Kuroda K, Baba T, Ichiki Y, Ono K, Yasuda M, Uramoto H, So T, Takenoyama M, Hanagiri T, Yasumoto K
  • Organizer: The 10th International Conference of tne International Mesothelinoma Interest Group
  • Place of Presentation: 国立京都国際会館京都
  • Year and Date: 20100831-0903
• [Presentation] T細胞受容体移入γδT細胞による養子免疫療法への応用 (2010)
  • Author(s): 重松義紀, 黒田耕志, 馬場哲郎, 永田好香, 下川秀彦, 小野憲司, 浦本秀隆, 竹之山光広, 花桐武志, 安元公正
  • Organizer: 第14回日本がん免疫学会総会
  • Place of Presentation: KKRホテル熊本
  • Year and Date: 20100722-23
• [Presentation] 肺癌に高発現する新規腫瘍抗原ribosomal protein L19の機能解析 (2010)
  • Author(s): 黒田耕志, 竹之山光広, 塩田広宣, 馬場哲郎, 重松義紀, 宗哲哉, 水上真紀子, 市来嘉伸, 小野憲司, 安田学, 菅谷将一, 浦本秀隆, 宗知子, 花桐武志, 安元公正
  • Organizer: 第27回日本呼吸器外科学会総会
  • Place of Presentation: 仙台国際センター仙台
  • Year and Date: 20100513-14
• [Presentation] 竹之山光広,花桐武志,安元公正:悪性胸膜中皮腫関連抗原の同定と機能解析 (2010)
  • Author(s): 重松義紀, 黒田耕志, 馬場哲郎, 宗哲哉, 安田学, 小野憲司, 浦本秀隆, 宗知子, 竹之山光広, 花桐武志, 安元公正
  • Organizer: 第27回日本呼吸器外科学会総会
  • Place of Presentation: 仙台国際センター仙台
  • Year and Date: 20100513-14
• [Presentation] 癌精巣抗原KK-LC-1を認識するT細胞受容体移入γδT細胞を用いた養子免疫療法への応用 (2010)
  • Author(s): 重松義紀, 塩田広宣, 黒田耕志, 馬場哲郎, 宗哲哉, 小野憲司, 浦本秀隆, 宗知子, 竹之山光広, 花桐武志, 安元公正
  • Organizer: 第110回日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場名古屋
  • Year and Date: 20100408-10
• [Presentation] 悪性胸膜中皮腫に対する腫瘍特異的免疫応答の解析 (2010)
  • Author(s): 竹之山光広
  • Organizer: 第28回産業医科大学学会総会
  • Place of Presentation: 産業医科大学ラマツィーホール北九州
  • Year and Date: 2010-10-12
• [Presentation] 腫瘍浸潤B細胞にて同定した悪性中皮腫関連抗原とその抗体価の臨床的意義 (2009)
  • Author(s): 重松義紀, 黒田耕志, 馬場哲郎, 宗哲哉, 小野憲司, 浦本秀隆, 宗知子, 竹之山光広, 花桐武志, 安元公正
  • Organizer: 第63回日本呼吸器学会
  • Place of Presentation: 北九州市国際会議場北九州
  • Year and Date: 20091126-27
• [Presentation] 石綿関連悪性腫瘍(胸膜中皮腫、肺癌)に対する新規バイオマーカー (2009)
  • Author(s): 安田学, 花桐武志, 重松義紀, 黒田耕志, 鬼塚貴光, 馬場哲郎, 宗哲哉, 小野憲司, 浦本秀隆, 宗知子, 竹之山光広, 安元公正
  • Organizer: 第63回日本呼吸器学会
  • Place of Presentation: 北九州国際会議場北九州
  • Year and Date: 20091126-27
• [Presentation] 肺癌における細胞障害性T細胞が認識する腫瘍抗原の同定 (2009)
  • Author(s): 竹之山光広, 花桐武志, 宗知子, 安田学, 市来嘉伸, 宗哲哉, 永田好香, 馬場哲郎, 重松義紀, 黒田耕志, 小野憲司, 浦本秀隆, 安元公正
  • Organizer: 第62回日本胸部外科学会定期学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20091011-14
• [Presentation] Immunotherapy for Lung Cancer (2009)
  • Author(s): Yasumoto K
  • Organizer: 11th Meeting of Chinese Lung Cancer Conference center of Wanli
  • Place of Presentation: Taida Hotel Tianjin, China
  • Year and Date: 20090828-30
• [Presentation] Diagnostic Markers for Malignant Pleural Mesothelioma Serum Antibody against Antigens Recognized by Antibodies Produced from Tumor Infiltrating B cells (2009)
  • Author(s): Shigematsu Y, Yasumoto K
  • Organizer: 2009 4th China Medicai Biotech Forum
  • Place of Presentation: New World Hotel Dalian, China
  • Year and Date: 20090808-10
• [Presentation] The identification of tumor antigens associated with asbestos-related lung cancer (2009)
  • Author(s): Hanagiri T, Yasuda M, Kuroda K, Shigematsu Y, Baba T, So T, Ono K, Uramoto H, So T, Takenoyama M, Yasumoto K
  • Organizer: 13th World Conference on Lung Cancer
  • Place of Presentation: W Hotel San Francisco, USA
  • Year and Date: 20090731-0804
• [Presentation] HLA発現異常を有する肺癌に対する腫瘍特異的Tリンパ球の解析 (2009)
  • Author(s): 黒田耕志, 竹之山光広, 馬場哲郎, 重松義紀, 宗哲哉, 市来嘉伸, 小野憲司, 安田学, 浦本秀隆, 宗知子, 花桐武志, 安元公正
  • Organizer: 第13回日本がん免疫学会総会
  • Place of Presentation: 北九州国際会議場北九州
  • Year and Date: 20090624-25
• [Presentation] 石綿関連肺癌に対する液性免疫応答の解析 (2009)
  • Author(s): 安田学, 花桐武志, 黒田耕志, 鬼塚貴光, 重松義紀, 馬場哲郎, 永田好香, 宗哲哉, 小野憲司, 浦本秀隆, 宗知子, 竹之山光広, 安元公正
  • Organizer: 第13回日本がん免疫学会総会
  • Place of Presentation: 北九州国際会議場北九州
  • Year and Date: 20090624-25
• [Presentation] 悪性胸膜中皮腫における腫瘍抗原の同定と新規腫瘍マーカーとしての意義 (2009)
  • Author(s): 重松義紀, 塩田広宣, 黒田耕志, 馬場哲郎, 永田好香, 水上真紀子, 市来嘉伸, 安田学, 竹之山光広, 花桐武志, 杉尾賢二, 安元公正
  • Organizer: 第109回日本外科学会定期学術集会
  • Place of Presentation: 福岡国際会議場、マリンメッセ福岡、福岡サンパレス福岡
  • Year and Date: 20090402-04