Development of novel classification of colorectal cancer for immunotherapy

• Project/Area Number: 26670581
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: National Cancer Center Japan (2015); Osaka University (2014)
• Principal Investigator: Nishikawa Hiroyoshi 国立研究開発法人国立がん研究センター, 先端医療開発センター, 分野長 (10444431)
• Co-Investigator(Renkei-kenkyūsha): DOKI Yuichiro 大阪大学, 大学院医学研究科, 教授 (20291445) ; HONDA Kenya 理化学研究所, 統合生命医科学研究センター, チームリーダー (60334231)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 免疫学 / 制御性T細胞 / 大腸癌 / エフェクターT細胞

Outline of Final Research Achievements

Human FOXP3+CD4+ T cells were composed of three distinct subpopulations: CD45RA+FOXP3lo+ naive Tregs, CD45RA-FOXP3hi+ effector Tregs, and CD45RA-FOXP3lo+ non-Tregs. While FOXP3+ T cell infiltration is a poor prognosis marker in many cancers, the significance of FOXP3 T cells in colorectal cancers(CRC) has been controversial. While CRC were commonly infiltrated by suppression-competent FOXP3hi Treg cells,they were divided into two groups by the degree of additional infiltration of FOXP3lo non-suppressive T cells. Such cells were induced by IL-12 and TGF-B and were correlated with tumor invasion of intestinal bacteria. Functionally distinct subpopulations of tumor-infiltrating FOXP3+ T cells oppositely contribute to determining CRC prognosis. Depletion of FOXP3hi Treg cells from tumor tissues to augment anti-tumor immunity can be an effective treatment of CRC and other cancers, while strategies to locally increase FOXP3lo non-Treg cells could be tumor-suppressive and -preventive.

Research Products

• [Journal Article] Hypomethylation of the Treg-specific demethylated region in FOXP3 is a hallmark of the regulatory T-cell subtype in adult T-cell leukemia (2016)
  • Author(s): Shimazu Y, Shimazu Y, Hishizawa M, Hamaguchi M, Nagai Y, Sugino N, Fujii S, Kawahara M, Kadowaki N, Nishikawa H, Sakaguchi S, Takaori-Kondo A
  • Journal Title: Cancer Immunol Res Volume: 4 Issue: 2 Pages: 136-145
  • DOI: 10.1158/2326-6066.cir-15-0148
  • Peer Reviewed
• [Journal Article] 制御性T細胞と免疫寛容―発がんからがん免疫療法へのかかわりー (2016)
  • Author(s): 西川博嘉
  • Journal Title: Annual Review 血液 Volume: 2016 Pages: 112-117
  • Peer Reviewed
• [Journal Article] 免疫チェックポイント阻害薬と他の免疫療法との併用の可能性 (2016)
  • Author(s): 藤岡優樹、西川博嘉
  • Journal Title: PHARMSTAGE Volume: 1 Pages: 39-48
  • Peer Reviewed
• [Journal Article] がん免疫における制御性T細胞 (2016)
  • Author(s): 杉山大介 西川博嘉
  • Journal Title: 腫瘍内科 Volume: 17 Pages: 94-97
  • NAID: 40020719723
  • Peer Reviewed
• [Journal Article] Overview: New Modality for Cancer Treatment. (2015)
  • Author(s): Nishikawa H.
  • Journal Title: Oncology Volume: Nov;8 9 Suppl 1 Issue: Suppl. 1 Pages: 33-35
  • DOI: 10.1159/000431063
  • Peer Reviewed
• [Journal Article] Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. (2015)
  • Author(s): 2.Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R, Nakayama E.
  • Journal Title: Clin Cancer Res. Volume: 21 Issue: 19 Pages: 4327-36
  • DOI: 10.1158/1078-0432.ccr-15-0357
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulatory T cells in cancer; can they be controlled? (2015)
  • Author(s): Adeegbe DO, Nishikawa H.
  • Journal Title: Immunotherapy Volume: 7(8) Issue: 8 Pages: 843-846
  • DOI: 10.2217/imt.15.52
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans. (2015)
  • Author(s): Miyara, M., et al.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 112 Issue: 23 Pages: 7225-7230
  • DOI: 10.1073/pnas.1508224112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ヒト制御性T細胞の解析 (2015)
  • Author(s): 西川博嘉、坂口志文
  • Journal Title: 医学のあゆみ Volume: 252 Pages: 69-74
  • Peer Reviewed
• [Journal Article] Visual View がん免疫療法のメカニズム (2015)
  • Author(s): 西川博嘉
  • Journal Title: Immuno-Oncology Frontier Volume: 1 Pages: 10-13
  • Peer Reviewed
• [Journal Article] 免疫療法におけるバイオマーカーと個別化医療 (2015)
  • Author(s): 竹内美子、西川博嘉
  • Journal Title: がん分子標的治療 Volume: 13 Pages: 20-23
  • Peer Reviewed
• [Journal Article] がん免疫療法における制御性T細胞の意義 (2015)
  • Author(s): 竹内美子、西川博嘉
  • Journal Title: 腫瘍内科 Volume: 16 Pages: 360-366
  • NAID: 40020629183
  • Peer Reviewed
• [Journal Article] 抗PD-1抗体ニボルマブの基礎と臨床効果 (2015)
  • Author(s): 竹内美子、西川博嘉
  • Journal Title: 医学のあゆみ Volume: 254 Pages: 777-783
  • Peer Reviewed
• [Journal Article] がん患者における免疫病態の最新知見と展望 (2015)
  • Author(s): 杉山大介、西川博嘉
  • Journal Title: Medical Science Digest Volume: 41 Pages: 8-10
  • Peer Reviewed
• [Journal Article] Detection of self-reactive CD8⁺ T cells with an anergic phenotype in healthy individuals. (2014)
  • Author(s): Maeda Y, Nishikawa H, Sugiyama D, Ha D, Hamaguchi M, Saito T, Nishioka M, Wing JB, Adeegbe D, Katayama I, Sakaguchi S.
  • Journal Title: Science Volume: 346 Issue: 6216 Pages: 1536-40
  • DOI: 10.1126/science.aaa1292
  • Peer Reviewed
• [Journal Article] Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. (2014)
  • Author(s): Mastumoto, M., Baba, A., Yokota, T., Nishikawa, H., Ohkawa, Y., Kayama, H., Kallies, A., Nut, S. L., Sakaguchi, S., Takeda, K., Kurosaki, T., and Baba, Y.
  • Journal Title: Immunity Volume: 41 Issue: 6 Pages: 1040-1051
  • DOI: 10.1016/j.immuni.2014.10.016
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory T cells in cancer immunotherapy (2014)
  • Author(s): Nishikawa H, Sakaguchi S
  • Journal Title: Curr Opin Immunol Volume: 27 Pages: 1-7
  • DOI: 10.1016/j.coi.2013.12.005
  • NAID: 130004696113
  • Peer Reviewed
• [Journal Article] Detection of T-cell responses to a ubiquitous cellular protein in autoimmune disease. (2014)
  • Author(s): Ito Y, Hashimoto M, Hirota K, Ohkura N, Morikawa H, Nishikawa H, Tanaka A, Furu M, Ito H, Fujii T, Nomura T, Yamazaki S, Morita A, Vignali D, Kappler J, Matsuda S, Mimori T, Sakaguchi N, Sakaguchi S.
  • Journal Title: Science Volume: 346 Issue: 6207 Pages: 363-8
  • DOI: 10.1126/science.1259077
  • Peer Reviewed
• [Journal Article] High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine (2014)
  • Author(s): Saito T, Wada H, Yamasaki M, Miyata H, Nishikawa H, Sato E, Kageyama S, Shiku H, Mori M, Doki Y.
  • Journal Title: Vaccine Volume: 32 Issue: 45 Pages: 5901-5907
  • DOI: 10.1016/j.vaccine.2014.09.002
  • Peer Reviewed
• [Journal Article] Vaccination With NY-ESO-1 Overlapping Peptides Mixed With Picibanil OK-432 and Montanide ISA-51 in Patients With Cancers Expressing the NY-ESO-1 Antigen (2014)
  • Author(s): Wada H, Isobe M, Kakimi K, Mizote Y, Eikawa S, Sato E, Takigawa N, Kiura K, Tsuji K, Iwatsuki K, Yamasaki M, Miyata H, Matsushita H, Udono H, Seto Y, Yamada K, Nishikawa H, Pan L, Venhaus R, Oka M, Doki Y, Nakayama E.
  • Journal Title: J Immunother Volume: 37(2) Issue: 2 Pages: 84-92
  • DOI: 10.1097/cji.0000000000000017
  • Peer Reviewed
• [Presentation] 制御性T細胞による免疫寛容誘導機構 -腫瘍免疫からのレッスン- (2016)
  • Author(s): 西川博嘉
  • Organizer: 第34回日本耳鼻咽喉科免疫アレルギー学会
  • Place of Presentation: 三重県鳥羽市
  • Year and Date: 2016-02-04
  • Invited
• [Presentation] 臨床の場におけるがん免疫療法 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第148回日本医学会シンポジウム 新しいがん免疫療法
  • Place of Presentation: 東京都文京区
  • Year and Date: 2015-12-25
• [Presentation] Regulatory T-cell suppression in tumors (2015)
  • Author(s): 西川博嘉
  • Organizer: 第44回日本免疫学会総会学術集会
  • Place of Presentation: 北海道札幌市
  • Year and Date: 2015-11-20
• [Presentation] 制御性T細胞を標的とするがん免疫治療の新たな展望 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第53回日本癌治療学会学術集会
  • Place of Presentation: 京都府京都市
  • Year and Date: 2015-10-22
• [Presentation] 慢性特発性間質性肺炎の新たなentityを形成する抗Mx1自己抗体の意義 (2015)
  • Author(s): 濱野芳匡、木田博、井原祥一、Lokesh Tripthi、広瀬雅樹、西川博嘉、本多修、水口賢司、富山憲幸、井上義一、熊ノ郷淳
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2015-10-22
• [Presentation] 腫瘍免疫と制御性T細胞 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2015-10-22
• [Presentation] CD4+Tregの病態への関与と疾患制御の可能性 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2015-10-22
• [Presentation] Accelerates Immuno-Oncology Research to Combat Cancers (2015)
  • Author(s): 西川博嘉
  • Organizer: Asia-Pacific Educational Center of Hematology and Oncology 2015 (APECHO 2015, Taiwan）
  • Place of Presentation: 台北
  • Year and Date: 2015-10-18
• [Presentation] 固形がん患者におけるTreg -ヒト化抗CCR4抗体投与による除去効果を中心に- (2015)
  • Author(s): 和田尚、土岐祐一郎、西川博嘉、中山睿一、上田龍三
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2015-10-09
• [Presentation] レナリドマイドは制御性T細胞の機能を抑制し抗腫瘍免疫応答を増強させる (2015)
  • Author(s): 杉山大介、竹内美子、西川博嘉
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2015-10-09
• [Presentation] 大腸癌に対する免疫応答の複雑性 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2015-10-09
• [Presentation] Anti-tumor immune responses in cancer therapy（がん治療における抗腫瘍免疫応答） (2015)
  • Author(s): 西川博嘉
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2015-10-08
• [Presentation] 制御性T細胞コントロールによる効果的ながん免疫療法開発 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第7回血液疾患免疫療法研究会学術集会
  • Place of Presentation: 東京都文京区
  • Year and Date: 2015-09-26
• [Presentation] 3+CD4+T-cell subpopulations distinctly control the prognosis of colorectal cancers. (2015)
  • Author(s): Takuro Saito, Hiroyoshi Nishikawa, Hisashi Wada, Masaki Mori, Yuichiro Doki, Shimon Sakaguchi
  • Organizer: The Inaugural International Cancer Immunotherapy Conference Translating Science Into Survival
  • Place of Presentation: 米国 ニューヨーク市
  • Year and Date: 2015-09-18
• [Presentation] Self-tumor-antigen-specific CD8 T cells were suppressed by regulatory T cells. (2015)
  • Author(s): Yuka Maeda, Hiroyoshi Nishikawa, Shimon Sakaguchi
  • Organizer: The Inaugural International Cancer Immunotherapy Conference Translating Science Into Survival
  • Place of Presentation: 米国 ニューヨーク市
  • Year and Date: 2015-09-18
• [Presentation] Phase la study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody,KW-0761,in cancer patients (2015)
  • Author(s): Koji Kurose, Yoshihiro Ohue, Hisashi Wada, Toshihiko Doi, Hiroyoshi Nishikawa, Mikio Oka, Ryuzo Ueda
  • Organizer: The Inaugural International Cancer Immunotherapy Conference Translating Science Into Survival
  • Place of Presentation: 米国 ニューヨーク市
  • Year and Date: 2015-09-16
• [Presentation] Role of regulatory T cell in inflammation-associated colorectal cancer;Friends or foes? (2015)
  • Author(s): 西川博嘉
  • Organizer: 第14回あわじしま感染症・免疫フォーラム
  • Place of Presentation: 兵庫県淡路市
  • Year and Date: 2015-09-09
• [Presentation] Regulatory T cells in tumor immunity and autoimmune disorders (2015)
  • Author(s): 西川博嘉
  • Organizer: Biomedicum, Helsinki Educational Seminar
  • Place of Presentation: フィンランド ヘルシンキ
  • Year and Date: 2015-08-31
• [Presentation] 大腸癌に影響を与えるFoxP3+T細胞と腸内細菌 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第36回日本炎症・再生医学会
  • Place of Presentation: 東京都港区
  • Year and Date: 2015-07-21
• [Presentation] 免疫チェックポイントの基礎 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第13回日本臨床腫瘍学会学術集会
  • Place of Presentation: 北海道札幌市
  • Year and Date: 2015-07-18
• [Presentation] 制御性T細胞の新たなコントロール法 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第13回日本臨床腫瘍学会学術集会
  • Place of Presentation: 北海道札幌市
  • Year and Date: 2015-07-16
• [Presentation] がん免疫療法の新展開 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第101回 日本消化器病学会総会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2015-04-24
• [Presentation] がん免疫療法と制御性T細胞 (2015)
  • Author(s): 西川博嘉
  • Organizer: 第10回日本がん分子標的治療学会トランスレーショナルリサーチワークショップ
  • Place of Presentation: 東京都
  • Year and Date: 2015-01-20
  • Invited
• [Presentation] がん免疫療法における制御性T細胞 (2014)
  • Author(s): 西川博嘉
  • Organizer: 第27回日本バイオセラピィ学会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2014-12-04 – 2014-12-05
  • Invited
• [Presentation] 制御性T細胞とがん免疫療法 (2014)
  • Author(s): 西川博嘉
  • Organizer: 第63回日本血液学会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2014-10-31 – 2014-11-02
  • Invited
• [Presentation] Regulatory T cells in anti-tumor immunity: Can they be controlled? (2014)
  • Author(s): Hiroyoshi Nishikawa
  • Organizer: 22nd Annual Cancer Immmunotherapy Symposium.
  • Place of Presentation: 米国ニューヨーク市
  • Year and Date: 2014-10-06 – 2014-10-08
  • Invited
• [Presentation] TCR repertoire reshaping emanating from therapeutic modalities involving Treg depletion and/or immune checkpoint blockade. (2014)
  • Author(s): Adeegbe D, Sugiyama D, Maeda Y, Ha D, Matsutani T, Nishikawa H and Sakaguchi S
  • Organizer: 22nd Annual Cancer Immmunotherapy Symposium.
  • Place of Presentation: 米国ニューヨーク市
  • Year and Date: 2014-10-06 – 2014-10-08
• [Presentation] Association between FoxP3+ T cells and regulatory T cells in colorectal cancer (2014)
  • Author(s): SaitoT, Nishikawa H, Wada H, Mori M, Doki Y and Sakaguchi S
  • Organizer: 22nd Annual Cancer Immmunotherapy Symposium.
  • Place of Presentation: 米国ニューヨーク市
  • Year and Date: 2014-10-06 – 2014-10-08
• [Presentation] 網羅的抗体反応測定法を用いた抗腫瘍免疫応答のモニタリング (2014)
  • Author(s): 西川博嘉
  • Organizer: 第42回日本臨床免疫学会
  • Place of Presentation: 東京都
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] Tregs in Cancer Immunotherapy (2014)
  • Author(s): Hiroyoshi Nishikawa
  • Organizer: 第73回日本癌学会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] 制御性T細胞は腫瘍抗原特異的CD8+T細胞に特徴的なアネルギー状態を誘導する (2014)
  • Author(s): 杉山大介、前田優香、西塔拓郎、西岡めぐみ、Danbee H、西川博嘉、坂口志文
  • Organizer: 第73回日本癌学会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] メラノーマ患者および健常人PBMC中のCD4+T細胞の単一細胞レベルでのレパートリー解析 (2014)
  • Author(s): 岸裕幸、小林英治、杉山大介、西川博嘉、坂口志文、村口篤
  • Organizer: 第73回日本癌学会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 大腸癌での制御性T細胞の予後への影響 (2014)
  • Author(s): 西塔拓郎、西川博嘉、和田 尚、坂口志文,森正樹、土岐裕一郎
  • Organizer: 第73回日本癌学会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Regulatory T cellを介したがん免疫応答制御の克服の可能性 (2014)
  • Author(s): 西川博嘉
  • Organizer: 第34回日本分子腫瘍マーカー研究会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-24
  • Invited
• [Presentation] Promotion of T cell dysfunction by regulatory T cells in tumor; mechanisms and insights (2014)
  • Author(s): Adeegbe D, Sugiyama D, Maeda Y, Ha D, Matsutani T, Nishikawa H and Sakaguchi S
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: 愛媛県松山市
  • Year and Date: 2014-07-30 – 2014-08-04
• [Presentation] Importance of controlling regulatory T cells for successful cancer immunotherapy (2014)
  • Author(s): Hiroyoshi Nishikawa
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: 愛媛県松山市
  • Year and Date: 2014-07-30 – 2014-08-01
  • Invited
• [Presentation] 制御性T細胞は腫瘍抗原特異的CD8+T細胞に特徴的なアネルギー状態を誘導する (2014)
  • Author(s): 前田優香、西川博嘉、杉山大介、西塔拓郎、西岡めぐみ、Danbee H、坂口志文
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: 愛媛県松山市
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] 制御性T細胞を標的としたがん免疫療法 (2014)
  • Author(s): 西川博嘉
  • Organizer: 第18回日本がん分子標的治療学会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2014-06-25 – 2014-06-27
  • Invited
• [Remarks] 大阪大学免疫学フロンティア研究センター
  • URL: http://www.ifrec.osaka-u.ac.jp/index.php