Elucidation of the condition of construction mechanisms of immunity on sentinel lymph nodes of patients with melanoma and development of novel immunotherapy

• Project/Area Number: 24591635
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Keio University
• Principal Investigator: SAKURAI TOSHIHARU 慶應義塾大学, 医学部, 助教 (20101933)
• Co-Investigator(Kenkyū-buntansha): YAGUCHI Tomonori 慶應義塾大学, 医学部, 助教 (40424163) ; KAWAKAMI Yutaka 慶應義塾大学, 医学部, 教授 (50161287)
• Research Collaborator: NAKAMURA Shoko 慶應義塾大学, 医学部, 助教 (20528228)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 悪性黒色腫 / センチネルリンパ節 / 免疫抑制機構 / TGF-b1 / がん免疫療法 / 免疫抑制 / TGF-β / 免疫病態 / 細胞分子機構

Outline of Final Research Achievements

In cancer patients, sentinel lymph nodes (SLNs) are crucial in the induction of antitumor T cells. However, in many cases, SLNs and tumors appear to be in immune-suppressive condition through mechanisms yet to be elucidated. In this study, the role of tumor-derived TGF-b1 in the generation of immunosuppressive microenvironments of tumors and SLNs was investigated.
These results demonstrate that overproduction of TGF-b1 is critical for the generation of immunosuppressive microenvironments in both tumors and SLNs, which may result in suppression of spontaneous antitumor CD8+ T-cell responses. Therefore, TGF-b1 is an attractive target for restoration of immunosuppressive condition in cancer patients.

Research Products

• [Journal Article] TGF-β1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression (2014)
  • Author(s): Nakamura S, Yaguchi T, Kawamura N, Kobayashi A, Sakurai T, Higuchi H, Takaishi H, Hibi T, Kawakami Y
  • Journal Title: J Immunother Volume: 37(2) Issue: 2 Pages: 63-72
  • DOI: 10.1097/cji.0000000000000011
  • Peer Reviewed / Open Access
• [Journal Article] Immune suppression and resistance mediated by constitutive activation of Wnt/β-catenin signaling in human melanoma cells (2012)
  • Author(s): Yaguchi T.
  • Journal Title: J Immunol. Volume: 189 Issue: 5 Pages: 2110-2117
  • DOI: 10.4049/jimmunol.1102282
  • Peer Reviewed
• [Journal Article] Biomarkers for cancer immunotherapy (2012)
  • Author(s): Kawakami Y, Kawase Y, Ohizumi A, Noji S, Sakurai T, Fujita T.
  • Journal Title: Nihon Rinsho. Volume: 70 Pages: 759-66
  • NAID: 40019297634
• [Journal Article] 【がん免疫学と免疫療法の新展開】 がん免疫病態と免疫動態の評価 (2012)
  • Author(s): 河上 裕, 谷口 智憲, 中村 公子, 川瀬 芳恵, 野路 しのぶ, 大泉 梓, 南雲 春菜, 長谷川 舞, 徐 明利, 岡本 正人, 桜井 敏晴, 藤田 知信
  • Journal Title: 血液フロンティア Volume: 22 Pages: 1183-1190
• [Presentation] 腫瘍浸潤T細胞は大腸癌の予後マーカーとなる (2014)
  • Author(s): 藤田 知信、徐 明利、ポピバノバ ボリヤナ、岡本 正人、桜井 敏晴、鳥越 俊彦、古畑 智久、杉浦 史哲、奥野 清隆、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(横浜）
  • Year and Date: 2014-09-27
• [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（東京）
  • Year and Date: 2014-09-25
• [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 (中国）
  • Year and Date: 2014-09-04
  • Invited
• [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)
  • Year and Date: 2014-08-01
• [Presentation] Immunosuppresive roles of local renin angiotensin system (RAS) in cancer microenvironments. (2013)
  • Author(s): Nakamura Kenta, Tomonori Yaguchi, Gaku Ohmura, Asuka Kobayasi, Naosi Kawamura, Juri Sugiyama, Toshiharu Sakurai, Yukiko Kiniwa, Ryuhei Okuyama, Yutaka Kawakami
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: パシフィコ横浜 （横浜）
• [Presentation] Strong correlation of tumor-infiltrating CD8+ and Foxp3+ T cells with favorable prognosis of patients with colon cancer (2013)
  • Author(s): Xu Mingli, Noji Shinobu, Okamoto Masato, Sakurai Toshiharu, Fujita Tomonobu, Torigoe Toshihiko, Sato Noriyuki, Sugiura Fumiaki, Okuno Kiyotaka, Hazama Shoichi, Oka Masaaki, Kawakami Yutaka
  • Organizer: 第42回日本免疫学会総会
  • Place of Presentation: 幕張メッセ （千葉）
• [Presentation] The high plasma IL6 and IL8 are biomarkers for predicting poor clinical outcome of cancer patients treated with peptide cancer vaccines (2013)
  • Author(s): Fujita Tomonobu, Noji Shinobu, Nagumo Haruna, Okamoto Masato, Sakurai Toshiharu, Noguchi Masanori, Matsueda Satoko, Itoh Kyogo, Hazama Shoichi, Oka Masaaki, Kawakami Yutaka
  • Organizer: 第42回日本免疫学会総会
  • Place of Presentation: 幕張メッセ （千葉）
• [Presentation] Tumor immunology Different tumor immunoenvironments among patients: Biomarkers and their modification for cancer treatments (2013)
  • Author(s): Kawakami Yutaka, Xu Mingli, Nagumo Haruna, Fujita Tomonobu, Okamoto Masato, Sakurai Toshiharu, Noji Shinobu, Sugiyama Juri, Hayakawa Taeko, Nishio Hiroshi, Yaguchi Tomonori
  • Organizer: 第42回日本免疫学会総会
  • Place of Presentation: 幕張メッセ （千葉）
• [Presentation] 能動免疫療法における免疫誘導・抗腫瘍効果を規定するバイオマーカーの検索 (2012)
  • Author(s): 川瀬芳恵、藤田知信、大泉梓、野路しのぶ、桜井敏晴、南雲春菜、徐明利、中山睿一、垣見和宏、鳥越俊彦、池田裕明、珠玖洋、岡本正人、河上裕
  • Organizer: 第16回日本がん免疫学会
  • Place of Presentation: 北海道大学学術交流会館
• [Presentation] 悪性黒色腫に異所性に発現するHistatin-1はin vivoで細胞運動能と免疫抑制能を亢進させる (2012)
  • Author(s): 谷口智憲、栗原智樹、後藤康文、伊藤有毅、守井賢二、小林明日香、西尾浩、住本秀敏、河上裕
  • Organizer: 第16回日本がん免疫学会
  • Place of Presentation: 北海道大学学術交流会館
• [Presentation] 悪性黒色腫で亢進するWnt/β-cateninシグナルは免疫抑制的で腫瘍を促進する微小環境を誘導する (2012)
  • Author(s): 谷口智憲、栗原智樹、後藤康文、伊藤有毅、守井賢二、小林明日香、西尾浩、住本秀敏、河上裕
  • Organizer: 第71回日本癌学会
  • Place of Presentation: ロイトン札幌