Systematic analysis of cellular signaling involved in the melanoma induced immunosuppression

• Project/Area Number: 25670506
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Keio University
• Principal Investigator: KAWAKAMI Yutaka 慶應義塾大学, 医学部, 教授 (50161287)
• Co-Investigator(Kenkyū-buntansha): TSUKAMOTO Nobuo 慶應義塾大学, 医学部, 助教 (20407117) ; YAGUCHI Tomonori 慶應義塾大学, 医学部, 助教 (40424163)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 悪性黒色腫 / がん免疫療法 / 免疫抑制 / 網羅的分子解析 / 分子標的治療薬 / 免疫療法 / 免疫制御 / 分子標的薬

Outline of Final Research Achievements

Immunotherapy is now known to be effective on melanoma, but not all the patients. One of the reasons is immunosuppression caused by melanoma cells. Understanding it's mechanism may lead to improvement of melanoma treatment. In this study, by systematic screening of molecules involved in the human melanoma induced immunosuppression using low molecular weight compound libraries and siRNA libraries, we found that TGF-β and MAPK signaling pathways are important for the human melanoma induced immunosuppression in both induction and effector phases of anti-melanoma specific T-cells. We identified cellular and molecular mechanisms in the TGF-β and MAPK induced immunosuppression. These results indicate that blockade of TGF-β or MAPK pathway may be useful for the improvement of current melanoma therapies, particularly for cancer immunotherapy.

Research Products

• [Journal Article] NUAK2 amplification coupled with PTEN deficiency promote melanoma development via CDK activation. (2015)
  • Author(s): Namiki T, Yaguchi T, Nakamura K, Valencia JC, Coelho SG, Yin L, Kawaguchi M, Vieira WD, Kaneko Y, Tanemura A, Katayama I, Yokozeki H, Kawakami Y, Hearing VJ.
  • Journal Title: Cancer Res. Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Absence of recognition of common melanocytic antigens by T cells isolated from the cerebrospinal fluid of a Vogt-Koyanagi-Harada patient . (2014)
  • Author(s): Abad S, Wieers G, Colau D, Wildmann C, Delair E, Dhote R, Brezin AP, Kawakami Y, Coulie PG, van der Bruggen P.
  • Journal Title: Molecular Vision. Volume: 20 Pages: 956-969
  • Peer Reviewed / Open Access
• [Journal Article] A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study). (2014)
  • Author(s): Hazama S, Nakamura Y, Tanaka H, Hirakawa K, Tahara K, Shimizu R, Ozasa H, Etoh R, Sugiura F, Okuno K, Furuya T, Nishimura T, Sakata K, Yoshimatsu K, Takenouchi H, Tsunedomi R, Inoue Y, Kanekiyo S, Shindo Y, Suzuki N, Yoshino S, Shinozaki H, Kamiya A, Furukawa H, Yamanaka T, Fujita T, Kawakami Y, Oka M.
  • Journal Title: J Transl Med. Volume: 12 Issue: 1 Pages: 108-108
  • DOI: 10.1186/1479-5876-12-108
  • Peer Reviewed / Open Access
• [Journal Article] Predictive Biomarkers for the Outcome of Vaccination of Five Therapeutic Epitope Peptides for Colorectal Cancer. (2014)
  • Author(s): Hazama S, Takenouchi H, Tsunedomi R, Iida M, Suzuki N, Iizuka N, Inoue Y, Sakamoto K, Nakao M, Shindo Y, Kanekiyo S, Tokumitsu Y, Yoshimura K, Maeda N, Maeda K, Maeda Y, Matsui H, Yoshino S, Nakamura Y, Fujita Y, Hamamoto Y, Okamoto M, Fujita T, Kawakami Y, Oka M.
  • Journal Title: Anticancer Res. Volume: 34 Pages: 4201-4206
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-induced immunosuppressive cascades and their reversal by molecular-targeted therapy. (2013)
  • Author(s): Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Tsukamoto N, Iwata-Kajihara T, Nakamura S, Nishio H, Satomi R, Kobayashi A, Tanaka M, Hoon Park J, Kamijuku H, Tsujikawa T, Kawamura N
  • Journal Title: Ann. N.Y. Acad. Sci., Volume: 1284(1) Issue: 1 Pages: 80-86
  • DOI: 10.1111/nyas.12094
  • Peer Reviewed
• [Journal Article] Improvement of cancer immunotherapy by combining molecular targeted therapy (2013)
  • Author(s): Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Iwata-Kajihara T, Nakamura S, Miyzaki J, Kawamura N, Hoon Park J, Popivanova B, Tsujikawa T
  • Journal Title: Frontiers in Oncology Volume: 36 Pages: 1-7
  • DOI: 10.3389/fonc.2013.00136
  • Peer Reviewed
• [Journal Article] Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases. (2013)
  • Author(s): Qu N, Xu M, Mizoguchi I, Furusawa J, Kaneko K, Watanabe K, Mizuguchi J, Itoh M,Kawakami Y, Yoshimoto T.
  • Journal Title: Clin Dev Immunol. Volume: 2013:968549 Pages: 1-13
  • DOI: 10.1155/2013/968549
  • Peer Reviewed
• [Presentation] 新規作用機序を有する抗PD-1抗体薬について (2015)
  • Author(s): 河上裕
  • Organizer: 東海がんプロフェッショナル養成基盤推進プラン 平成26年度薬剤師セミナー
  • Place of Presentation: 名古屋大学医学部
  • Year and Date: 2015-03-14
• [Presentation] In vivo anti-tumor effects of berberine through augmentation of anti-tumor T-cell responses (2014)
  • Author(s): Kamijuku H, Tsukamoto N, Park JH, Liu H, Kawakami Y.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-12
• [Presentation] Immunosuppression by downstream molecules regulated by aryl hydrocarbon receptor (AhR) in tumor microenvironment (2014)
  • Author(s): Tsukamoto N, Park JH, Kamijuku H, Kawakami Y.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-12
• [Presentation] Effective cancer immunotherapy for human melanoma by combination of BRAF inhibitor and Toll-like receptor 7 agonist. (2014)
  • Author(s): Nakamura K, Yaguchi T, Popivanova B, Murata M, Mikoshiba A, Kiniwa Y, Okuyama R, Kawakami Y.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-12
• [Presentation] 腫瘍免疫学とがん免疫療法の最近の進歩 (2014)
  • Author(s): 河上裕
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-12
• [Presentation] Development of Immunotherapy based on the immunological chracteristics of Gynecologic Cancers (2014)
  • Author(s): Kawakami Y, Sugiyama J, Nishio H, Hayakawa T, Iwata T, Aoki D, Yaguchi T.
  • Organizer: The 19thJapan-Korea Cancer Research Workshop
  • Place of Presentation: Jeju, Korea
  • Year and Date: 2014-11-29
• [Presentation] Combination Immunotherapy Based on the Cancer Cell's Characteristics and Patients' Immune Status. (2014)
  • Author(s): Kawakami Y
  • Organizer: The 45thInternational Symposium of The Princess Takamatsu Cancer Research Fund,
  • Place of Presentation: Palace Hotel Tokyo/Japan
  • Year and Date: 2014-11-18
• [Presentation] Enhanced anti-tumor effects of the PD-1/PD-L1 blockade by combining a highly absorptive form of NF-kB/STAT3 inhibitor curcumin. (2014)
  • Author(s): Hayakawa T, Sugiyama J, Yaguchi T, Imaizumi A, Kawakami Y.
  • Organizer: The 29th Society for Immunotherapy of Cancer Annual Meeting
  • Place of Presentation: National Harbor, MD, USA
  • Year and Date: 2014-11-06
• [Presentation] 腫瘍免疫学とがん免疫療法の最近の進歩 (2014)
  • Author(s): 河上裕
  • Organizer: Immuno-Oncology Seminar「メラノーマ治療の新展開 抗PD-1抗体：オプジーボの適正使用に向けて」
  • Place of Presentation: ホテル日航東京１階ペガサズ
  • Year and Date: 2014-10-19
• [Presentation] 分子標的薬併用による効果的な個別化がん免疫療法 (2014)
  • Author(s): 河上裕、早川妙香、中村謙太、ポピバノバ ボリヤナ、杉山重里、西尾浩、谷口智憲
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-27
• [Presentation] がん免疫病態とがん免疫療法 (2014)
  • Author(s): 河上裕
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-27
• [Presentation] クルクミン併用による免疫抑制改善効果を介した免疫チェックポイント阻害療法の効果増強 (2014)
  • Author(s): 早川 妙香、杉山 重里、谷口 智憲、今泉 厚、河上 裕
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-26
• [Presentation] 腫瘍免疫におけるT細胞の意義とその制御によるがん治療 (2014)
  • Author(s): 河上裕
  • Organizer: 第42回日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル
  • Year and Date: 2014-09-25
• [Presentation] がんワクチン療法における治療前のIL6・IL8高値と予後不良は関連する (2014)
  • Author(s): 南雲 春菜、藤田 知信、野路 しのぶ、岡本 正人、桜井 敏晴、澤田 雄、中面 哲也、野口 正典、松枝 智子、伊東 恭悟、硲 彰一、岡 正朗、河上 裕
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25
• [Presentation] 局所性Renin-Angiotensin systemの阻害による、がん関連線維芽細胞や骨髄系免疫細胞の制御を介したPD-1/PD-L1免疫チェックポイント阻害療法の効果増強 (2014)
  • Author(s): 中村謙太、谷口智憲、大村学、小林明日香、川村直、杉山重里、桜井敏晴、木庭幸子、奥山隆平、河上裕
  • Organizer: 第42回日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル
  • Year and Date: 2014-09-25
• [Presentation] がん治療における免疫バイオマーカー (2014)
  • Author(s): 河上裕、藤田知信、ポピバノバ ボリヤナ、南雲春菜、鳥越俊彦、奥野清隆、硲彰一、伊東恭悟
  • Organizer: 第34回日本分子腫瘍マーカー研究会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-24
• [Presentation] がん免疫状態の個体差とがん治療反応性 (2014)
  • Author(s): 河上裕
  • Organizer: 第６回血液疾患免疫療法研究会学術集会
  • Place of Presentation: 京都大学医学部校内・芝蘭会館 山内ホール
  • Year and Date: 2014-09-06
• [Presentation] Cancer-induced differential immune-status among patients and it'smodification for effective cancer treatment (2014)
  • Author(s): Kawakami Y, Popivanova B, Nagumo H, Muramatsu R, Shinobu Noji, Xu M, Fujita T, Okamoto M, Sakurai T, Sugiyama J, Hayakawa T, Satomi R, Nishio H, Yaguchi T.
  • Organizer: Cold Spring Harbor Asia,Frontiers of Immunology in Health and Diseases
  • Place of Presentation: Suzhou, China
  • Year and Date: 2014-09-04
  • Invited
• [Presentation] 高吸収クルクミン併用による免疫抑制改善効果を介した免疫チェックポイント阻害療法の効果増強 (2014)
  • Author(s): 早川妙香、杉山重里、今泉厚、谷口智憲、河上裕
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール、愛媛県
  • Year and Date: 2014-08-01
• [Presentation] 局所性Renin-Angiotensin systemの阻害による、がん関連線維芽細胞や骨髄系免疫細胞の制御を介したPD-1/PD-L1免疫チェックポイント阻害療法の効果増強 (2014)
  • Author(s): 中村謙太、谷口智憲、大村学、小林明日香、川村直、杉山重里、桜井敏晴、木庭幸子、奥山隆平、河上裕
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール、愛媛県
  • Year and Date: 2014-08-01
• [Presentation] がんペプチドワクチン後予後予測マーカーとしての治療前血中IL6・IL8の意義 (2014)
  • Author(s): 藤田知信、野路しのぶ、南雲春菜、岡本正人、桜井敏晴、澤田雄、吉川聡明、下村真菜美、中面哲也、野口正典、松枝智子、伊東恭悟、硲彰一、竹之内寛子、岡正朗、河上裕
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール、愛媛県
  • Year and Date: 2014-07-31
• [Presentation] ヒト末梢血移入マウスMHC class I/IIノックアウトNOGマウスを用いたヒト腫瘍免疫応答のin vivo解析 (2014)
  • Author(s): 谷口智憲、小林明日香、片野いくみ、河裕遥、猪爪隆史、伊藤守、河上裕
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール、愛媛県
  • Year and Date: 2014-07-31
• [Presentation] CD155-TIGIT interactiono is an immune checkpoit regulating antimelanoma immune responses (2014)
  • Author(s): 猪爪隆史、谷口智憲、古田潤平、原田和俊、伊藤守、河上裕、島田眞路
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール、愛媛県
  • Year and Date: 2014-07-31
• [Presentation] Cancer induced differential immunoenvironments: Biomarkers and their modification by targeting signaling molecules, The 8thMiltenyi Cordeliers Meeting onImmunochemotherapy (2014)
  • Author(s): Yutaka Kawakami
  • Organizer: Centre de Recherche des Cordeliers (CRC),
  • Place of Presentation: Paris,France,
  • Year and Date: 2014-07-04
  • Invited
• [Presentation] Combinatorial immunotherapy based on the cancer cell characteristics and patients' immune status. (2014)
  • Author(s): Yutaka Kawakami
  • Organizer: The 12th CIMT Annual Meeting
  • Place of Presentation: Hilton Hotel in Mainz, Germany
  • Year and Date: 2014-05-06
  • Invited
• [Presentation] ヒトがん免疫病態の解明と免疫バイオマーカーの同定 (2013)
  • Author(s): 河上裕、徐明利、谷口智憲、野路しのぶ、南雲春菜、岡本正人、桜井敏晴、藤田知信、鳥越俊彦、佐藤昇志、中面哲也、垣見和宏、池田裕明、珠玖洋、奥野清隆、杉浦史哲、中山睿一、硲彰一、岡正朗、伊東恭悟,
  • Organizer: 第17回日本がん免疫学会
  • Place of Presentation: ANAクラウンプラザホテル宇部、山口県
• [Presentation] CD155はメラノーマ細胞に発現され、PD-L1と協調的にメラノーマ特異的CTLの活性化を抑制する (2013)
  • Author(s): 猪爪隆史、古田潤平、谷口智憲、河上裕、島田眞路
  • Organizer: 第17回日本がん免疫学会
  • Place of Presentation: ANAクラウンプラザホテル宇部、山口県
• [Presentation] 悪性黒色腫に異所性に発現するHistatin-1は樹状細胞を抑制し、がん免疫回避に関与する (2013)
  • Author(s): 谷口智憲
  • Organizer: 第23回日本樹状細胞研究会
  • Place of Presentation: 国立京都国際会館、京都府
• [Presentation] Reversal of Cancer Induced Immunosuppression by Targeting Signaling Molecules in Cancer and Immune Cells (2013)
  • Author(s): Yutaka Kawakami
  • Organizer: The 4thJSH International Symposium 2013
  • Place of Presentation: 大和屋本店、愛媛県
  • Invited
• [Presentation] STK24 mediates immunosuppressive and tumor promoting conditions in tumor microenvironment (2013)
  • Author(s): 川村直、住本秀敏、谷口智憲、辻川敬裕、守井賢二、小林明日香、河上裕
  • Organizer: 第40回日本臨床免疫学会
  • Place of Presentation: 京王プラザホテル、東京都
• [Presentation] がんの免疫病態とがん免疫療法 (2013)
  • Author(s): 河上 裕
  • Organizer: 第72回日本癌学会
  • Place of Presentation: パシフィコ横浜、神奈川県
• [Presentation] STAT3は腫瘍浸潤マクロファージの免疫抑制活性に必須である (2013)
  • Author(s): 住本 秀敏、岩田-梶原 知子、竹田 潔、河上 裕
  • Organizer: 第72回日本癌学会
  • Place of Presentation: パシフィコ横浜、神奈川県
• [Presentation] がん免疫療法の新展開： 最近の進歩と将来展望 (2013)
  • Author(s): 河上 裕
  • Organizer: 第72回日本癌学会
  • Place of Presentation: パシフィコ横浜、神奈川県
• [Presentation] Different immunoenvironments among cancer patients-Possible Biomarkers and modification for effective cancer treatments. (2013)
  • Author(s): Yutaka Kawaami, Mingli Xu, haruna Nagumo, Tomonobu Fujita, Masato Okamoto, Toshiharu Sakurai, Shinobu Noji, Juri Sugiyama, Taeko Hayakawa, Hiroshi Nishio, Tomonori Yaguchi,
  • Organizer: 2013Cold Spring Harbor Conferences Asia, Tumor Immunolgy & Immunotherapy
  • Place of Presentation: Suzhou Dushu Lake Conference Center 蘇州、中国
  • Invited
• [Book] Cancer Induced Immunosuppression and its Modulation by Signal Inhibitors in “Resistance of cancer cells to CTL-mediated immunotherapy” Eds: Chouaib S and Bonavida B, (2015)
  • Author(s): Kawakami Y, Qian L, Kawamura N, Miyazaki J, Tsubota K, Kinoshita T, Nakaura K, Ohmura G, Satomi R, Sugiyama J, Nishio H, Hayakawa T, Popivanova B, Nuchsupha S, Liu TH, Kamijuku H, Kudo-Saito C, Tsukamoto N, Sakurai T, Fujita T, Yaguchi T.
  • Publisher: Springer
• [Book] Development of personalized combination cancer immunotherapy based on the patients’ immune status in “Inflamamtion and immunity in cancer ” Eds:Tsukasa Seya, Keiko Udaka, Misako Matsumoto, Noriyuki Sato, (2015)
  • Author(s): Kawakami Y, Qian L, Kawamura N, Miyazaki J, Nagumo H, Tsubota K, Kinoshita , Nakamura K, Ohmura G, Satomi R, Sugiyama J, Nishio H, Hayakawa T, Popivanova B, Nuchsupha S, Liu TH, Kamijuku H, Kudo-Saito C, Tsukamoto N, Sakurai T, Fujita T, Yaguchi T.
  • Publisher: Springer
• [Book] Intratumoral Injection of BCG-CWS-Pretreated Dendritic Cells Following Tumor Cryoablation.in “Cancer Vaccines Methods and Protocols” Eds, Michael J.P., Patricia D. (2014)
  • Author(s): 1.Kawamura N, Udagawa M, Fujita T, Sakurai T, Yaguchi T, Kawakami Y
  • Publisher: Human Press
• [Book] The Potential of Using Induced Pluripotent Stem Cells in Skin Diseases. in "Cell and Molecular Biology and Imaging of Stem Cells" Eds, Heide Schatten (2014)
  • Author(s): Ohta S, Veraitch O, Okano H, Ohyama M, Kawakami Y
  • Publisher: John Wiley & Sons, Inc.
• [Book] Combination immunotheapy based on the cancer cell’s characteristics and patients’ immune status. In recent advances in cancer immunotherapy, Eds, Sakaguchi S, Wolchok JD, Heike Y, Kanakura Y, Kawakami Y, Sugiyama H. (2014)
  • Author(s): Kawakami Yutaka
  • Publisher: Takamutsu Cancer Research Fund, Tokyo
• [Book] Roles of signaling pathways in cancer cells and immune cells in generation of immunosuppressive tumor associated microenvironments. in “The Tumor Immunoenvironment” Eds, Michael Shurin, Anatoli Malyguine, Viktor Umansky, (2013)
  • Author(s): 1. Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Tsukamoto N, Iwata-Kajihara T, Nakamura S, Nishio H, Satomi R, Kobayashi A, Tanaka M, Kamijuku H, Tsujikawa T, Kawamura N.
  • Publisher: Springer Science.
• [Remarks] 慶應義塾大学医学部 先端医科学研究所 細胞情報研究部門
  • URL: http://keiocancer.com/