Generation of individualized cancer immuno-therapy independent of HLA-haplotypes

• Project/Area Number: 15H04308
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: University of Toyama
• Principal Investigator: Kishi Hiroyuki 富山大学, 大学院医学薬学研究部(医学), 准教授 (60186210)
• Co-Investigator(Kenkyū-buntansha): 小澤 龍彦 富山大学, 大学院医学薬学研究部(医学), 助教 (10432105) ; 村口 篤 富山大学, 大学院医学薬学研究部(医学), 名誉教授 (20174287)
• Co-Investigator(Renkei-kenkyūsha): HAMANA Hiroshi 富山大学, 大学院医学薬学研究部(医学), 客員准教授 (90551549) ; NISHIKAWA Hiroyoshi 国立がん研究センター, 先端医療開発センター, 免疫TR分野長 (10444431)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2016: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: Tumor / T cells / T cell receptor / HLAハプロタイプ / 腫瘍浸潤リンパ球 / TCR / T細胞受容体 / 免疫学 / 抗腫瘍効果 / HLA / ハプロタイプ / 癌 / Ｔ細胞 / 単一細胞解析

Outline of Final Research Achievements

T cells play important roles to suppress cancer generation in vivo. Recently, cancer therapy using T cells has been studied. T cells recognize the complex of cancer antigens and HLA molecules on cancer cells and kill them. The structure of HLA molecules are different in individual persons and T cells from a person whose HLA haplotype is different from a patient's HLA haplotype can not be used for the treatment of the patient. Major Japanese populations have HLA-A2 or A24 molecules. Thus, T cells recognizing cancer antigens in the context of HLA-A2 or A24 are studied, but those recognizing other HLA molecules are not. In this study, we have developed the method to find cancer-specific T cells independently of HLA haplotypes.

Research Products

• [Int'l Joint Research] Dana-Farber Cancer Institute(米国)
• [Int'l Joint Research] マニトバ大学(カナダ)
• [Journal Article] Identification of Tumoricidal TCRs from Tumor-Infiltrating Lymphocytes by Single-Cell Analysis (2018)
  • Author(s): Shitaoka Kiyomi、Hamana Hiroshi、Kishi Hiroyuki、Hayakawa Yoshihiro、Kobayashi Eiji、Sukegawa Kenta、Piao Xiuhong、Lyu Fulian、Nagata Takuya、Sugiyama Daisuke、Nishikawa Hiroyoshi、Tanemura Atsushi、Katayama Ichiro、Murahashi Mutsunori、Takamatsu Yasushi、Tani Kenzaburo、Ozawa Tatsuhiko、Muraguchi Atsushi
  • Journal Title: Cancer Immunology Research Volume: 6 Issue: 4 Pages: 378-388
  • DOI: 10.1158/2326-6066.cir-17-0489
  • Peer Reviewed / Open Access
• [Journal Article] Bladder cancer-associated cancer-testis antigen-derived long peptides encompassing both CTL and promiscuous HLA class II-restricted Th cell epitopes induced CD4+ T cells expressing converged T-cell receptor genes in vitro (2018)
  • Author(s): Tsuruta Miki、Ueda Shohei、Yew Poh Yin、Fukuda Isao、Yoshimura Sachiko、Kishi Hiroyuki、Hamana Hiroshi、Hirayama Masatoshi、Yatsuda Junji、Irie Atsushi、Senju Satoru、Yuba Eiji、Kamba Tomomi、Eto Masatoshi、Nakayama Hideki、Nishimura Yasuharu
  • Journal Title: OncoImmunology Volume: 7 Issue: 4 Pages: 1415687-1415687
  • DOI: 10.1080/2162402x.2017.1415687
  • Peer Reviewed / Open Access
• [Journal Article] Highly functional T-cell receptor repertoires are abundant in stem memory T cells and highly shared among individuals (2017)
  • Author(s): Miyama Takahiko、Kawase Takakazu、Kitaura Kazutaka、Chishaki Ren、Shibata Masashi、Oshima Kumi、Hamana Hiroshi、Kishi Hiroyuki、Muraguchi Atsushi、Kuzushima Kiyotaka、Saji Hiroh、Shin-I Tadasu、Suzuki Ryuji、Ichinohe Tatsuo
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 668-668
  • DOI: 10.1038/s41598-017-03855-x
  • Peer Reviewed / Open Access
• [Journal Article] Association Between High-Avidity T-Cell Receptors, Induced by α-Fetoprotein-Derived Peptides, and Anti-Tumor Effects in Patients With Hepatocellular Carcinoma (2017)
  • Author(s): Nakagawa H, Mizukoshi E, Kobayashi E, Tamai T, Hamana H, Ozawa T, Kishi H, Kitahara M, Yamashita T, Arai K, Terashima T, Iida N, Fushimi K, Muraguchi A, Kaneko S
  • Journal Title: Gastroenterology Volume: 152 Pages: 1395-1406
  • Peer Reviewed
• [Journal Article] A novel, rapid and efficient method of cloning functional antigen-specific T-cell receptors from single human and mouse T-cells (2016)
  • Author(s): Hamana H, Shitaoka K, Kishi H, Ozawa T, Muraguchi A.
  • Journal Title: Biochem Biophys Res Commun. Volume: 474 Pages: 709-714
  • Peer Reviewed
• [Journal Article] Immunological features of T cells induced by human telomerase reverse transcriptase-derived peptides in patients with hepatocellular carcinoma. (2015)
  • Author(s): E Mizukoshi, H Nakagawa, M Kitahara, T Yamashita, K Arai, H Sunagozaka, K Fushimi, E Kobayashi, H Kishi, A Muraguchi, S Kaneko.
  • Journal Title: Cancer Lett Volume: 364 Issue: 2 Pages: 98-105
  • DOI: 10.1016/j.canlet.2015.04.031
  • Peer Reviewed / Open Access
• [Journal Article] Identification of broadly conserved cross-species protective Leishmania antigen and its responding CD4 + T cells (2015)
  • Author(s): Z. Mou, J. Li, T. Boussoffara, H. Kishi, H. Hamana, P. Ezzati, C. Hu, W. Yi, D. Liu, F. Khadem, I. Okwor, P. Jia, K. Shitaoka, S. Wang, M. Ndao, C. Petersen, J. Chen, S. Rafati, H. Louzir, A. Muraguchi, J. a Wilkins, and J. E. Uzonna,
  • Journal Title: Science Translational Medicine Volume: 7 Issue: 310 Pages: 1-13
  • DOI: 10.1126/scitranslmed.aac5477
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Time-scale analysis of interplay between immunogenic tumor and immune response. (2017)
  • Author(s): Mojic M, Shitaoka K, Kishi H, Muraguchi A, Tahara H, Hayakawa Y.
  • Organizer: 5th Annual Meeting of the International Cytokine and Interferon Society (ICIS)2017
  • Int'l Joint Research
• [Presentation] 乳がん浸潤リンパ球の迅速・簡便TCRレパートリー解析． (2017)
  • Author(s): 浜名 洋，長田拓哉，下岡清美，祐川健太，小澤龍彦，村口 篤，岸 裕幸．
  • Organizer: 第21回日本がん免疫学会学術総会
• [Presentation] ヒト大腸がんにおける腫瘍浸潤CD8+T細胞のクロナリティと腫瘍反応性の解析． (2017)
  • Author(s): 藤井啓介，宮原慶裕，問山裕二，井上靖浩，浜名 洋，遠藤洋子，楠 正人，井上正宏，岸 裕幸，珠玖 洋．
  • Organizer: 第21回日本がん免疫学会学術総会
• [Presentation] 単一細胞TCRレパトア解析による，HLA及び抗原に依存しない，腫瘍特異的TCRの取得． (2017)
  • Author(s): 岸 裕幸．
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] ヒト大腸がんにおける腫瘍浸潤CD8+T細胞のクロナリティと腫瘍反応性の解析． (2017)
  • Author(s): 藤井啓介，宮原慶裕，問山裕二，井上靖浩，浜名 洋，遠藤洋子，楠 正人，井上正宏，岸 裕幸，珠玖 洋．
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] びまん性大細胞型B細胞リンパ腫における腫瘍浸潤CD8+Tリンパ球の解析． (2017)
  • Author(s): 村橋睦了，浜名 洋，岸 裕幸，山口 類，宮野 悟，緒方久修，岡崎利彦，佐々木秀法，宮本将平，谷憲三朗，大西秀哉，高松 泰，中西洋一．
  • Organizer: 第9回血液疾患免疫療法学会学術集会
• [Presentation] TCR repertoire analysis of antigen-specific T cells using immunospot array assay on a chip (T-ISAAC) technology. (2017)
  • Author(s): Kobayashi E, Ozawa T, Hamana H, Lyu F, Muraguchi A, Kishi H.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] T cell receptor (TCR) gene cloning from tumor infiltrating lymphocytes of breast cancer patients toward TCR gene therapy. (2017)
  • Author(s): Hamana H, Nagata T, Shitaoka K, Sukegawa K, Ozawa T, Kobayashi E, Muraguchi A, Kishi H.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Majority of tumor infiltrating lymphocytes in B16F10 melanoma recognized tumor-associated antigens, but not melanoma-associated antigens or neoantigens. (2017)
  • Author(s): Shitaoka K, Hamana H, Kobayashi E, Ozawa T, Hayakawa Y, Muraguchi A, Kishi H.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] T cell receptor repertoire of PD-1+CD137+ and PD1-CD137- tumor infiltrating lymphocytes in various cancers. (2017)
  • Author(s): Takahashi Y, Nagata T, Sukegawa K, Hamana H, Kishi H.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Tumor-specific CTL’s reduced clonality and proliferation index, not the inhibitory immune checkpoint expression, as hallmarks of B16 melanoma immune evasion. (2017)
  • Author(s): Mojic M, Shitaoka K, Kishi H, Muraguchi A, Tahara H, Hayakawa Y.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Phenotypic and clonality analysis of tumor-reactive CD8+ T cells among TILs in human colorectal tumor tissue. (2017)
  • Author(s): Fujii K, Miyahara Y, Toiyama Y, Inoue Y, Hamana H, Endo Y, Kusunoki M, Inoue M, Kishi H, Shiku H.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] TCR repertoire analysis of OVA-specific T-cells infiltrating OVA-expressing-melanoma during tumor progression (2016)
  • Author(s): Lyu F, Shitaoka K, Hamana H, Hayakawa Y, Kishi H, Muraguchi A
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] TCR repertoire of CD4+CD25+CD137+Foxp3+ tumor infiltrating lymphocytes in mice (2016)
  • Author(s): Kishi H, Hamana H, Shitaoka K, Lyu F, Ozawa T, Muraguchi A
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] T cell receptor obtained from tumor-infiltrating lymphocytes without using tumor-specific antigens exhibits cytotoxicity to tumors in vitro and in vivo (2016)
  • Author(s): Shitaoka K, Kishi H, Hamana H, Hayakawa Y, Ozawa T, Muraguchi A
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] A rapid and easy system for cDNAs cloning of antigen specific TCRs from single human and mouse T-cells within 4 days (2016)
  • Author(s): Hamana H, Kishi H, Shitaoka K, Ozawa T, Muraguchi A
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] 腫瘍浸潤リンパ球の単一細胞解析による腫瘍特異的TCRの同定および治療への応用（担癌マウスモデル） (2016)
  • Author(s): 岸 裕幸、村口 篤
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] CT26腫瘍局所浸潤CD8+T細胞のTCRレパトア解析と認識エピトープの同定 (2016)
  • Author(s): 藤井啓介，宮原慶裕，村岡大輔，下岡清美，浜名 洋，岸 裕幸，珠玖 洋
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] A rapid and easy system for screening of antigen-specific TCRs (2016)
  • Author(s): Hamana H, Kishi H, Shitaoka K, Piao X, Ozawa T, Muraguchi A
  • Organizer: 2016 International Congress of Immunology
  • Place of Presentation: Melbourne (Australia)
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] Identification of tumor-specific T cell receptors of primary tumor-infiltrating lymphocytes (TILs) from B16F10 melanoma-bearing mice at single cell levels (2016)
  • Author(s): Shitaoka K, Hamana H, Kishi H, Ozawa T, Muraguchi A
  • Organizer: 2016 International Congress of Immunology
  • Place of Presentation: Melbourne (Australia)
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] びまん性大細胞型B細胞リンパ腫における腫瘍浸潤CD8+Tリンパ球由来T細胞受容体および腫瘍微小環境の解析 (2016)
  • Author(s): 村橋睦了，浜名 洋，松本太一，鍋島一樹，猪狩洋介，佐々木秀法，原 周司，谷 憲三朗，岸 裕幸，高松 泰
  • Organizer: 第14回日本臨床腫瘍学会学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2016-07-28
• [Presentation] B16F10メラノーマ浸潤リンパ球の単一細胞解析による、がん特異的Ｔ細胞の同定およびTCR遺伝子治療の試み (2016)
  • Author(s): 下岡清美、浜名 洋、呂 福蓮、小澤龍彦、早川芳弘、岸 裕幸、村口 篤
  • Organizer: 第20回日本がん免疫学会総会
  • Place of Presentation: 大阪国際交流センター（大阪府大阪市）
  • Year and Date: 2016-07-27
• [Presentation] CT26腫瘍局所浸潤CD8+ T細胞のTCRレパトア解析と認識エピトープの同定 (2016)
  • Author(s): 藤井啓介、宮原慶裕、村岡大輔、下岡清美、浜名 洋、岸 裕幸、珠玖 洋
  • Organizer: 第20回日本がん免疫学会総会
  • Place of Presentation: 大阪国際交流センター（大阪府大阪市）
  • Year and Date: 2016-07-27
• [Presentation] Identification of tumor-specific T cell receptors from primary tumor-infiltrating lymphocytes (TILs) obtained from B16F10 melanoma-bearing mice. (2015)
  • Author(s): 5) Shitaoka K*, Kishi H, Hamana H, Ozawa T, Muraguchi A.
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌．
  • Year and Date: 2015-11-18
• [Presentation] Single Cell Analysis of Antigen Receptors of Lymphocytes for Tumor Immunology and Immunotherapy. (2015)
  • Author(s): Kishi H.
  • Organizer: The Korean Association of Immunologists 2015 Fall Conference
  • Place of Presentation: 韓国 ソウル
  • Year and Date: 2015-11-12
  • Int'l Joint Research / Invited
• [Presentation] プライマリー腫瘍浸潤リンパ球を用いた腫瘍特異的T細胞受容体同定の試み (2015)
  • Author(s): 岸 裕幸，村口 篤
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 悪性リンパ腫における腫瘍浸潤CD8+Tリンパ球の解析 (2015)
  • Author(s): 4) 村橋睦了，岸 裕幸，松本太一，原 周司，村口 篤，田村和夫，谷憲三朗
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 悪性リンパ腫における腫瘍浸潤CD8+Tリンパ球の解析 (2015)
  • Author(s): 岸 裕幸，村橋睦了，浜名 洋，松本太一，原 周司，猪狩洋介，石塚賢治，高松 泰，田村和夫，谷憲三朗，村口 篤．
  • Organizer: 第7回血液疾患免疫療法研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-09-26
• [Remarks] 富山大学大学院医学薬学研究部 免疫学講座
  • URL: http://www.med.u-toyama.ac.jp/immuno/top.html