Immunomodulation of ovarian clear cell carcinoma by targeting HNF-1 beta pathway

• Project/Area Number: 15K10731
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Keio University
• Principal Investigator: Fujita Tomonobu 慶應義塾大学, 医学部(信濃町), 助教 (20199334)
• Co-Investigator(Kenkyū-buntansha): 岩田 卓 慶應義塾大学, 医学部(信濃町), 講師 (30296652) ; 河上 裕 慶應義塾大学, 医学部(信濃町), 教授 (50161287)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 卵巣癌 / 免疫療法 / 卵巣明細胞腺癌 / 免疫抑制 / がん免疫療法 / 明細胞腺がん / がん微小環境 / 免疫抑制解除 / HNF-1β / 腫瘍内浸潤リンパ球 / 癌免疫抑制環境制御

Outline of Final Research Achievements

We have evaluated immunopathology of human ovarian clear cell carcinoma (OCCC), which generally produces high amounts of immunosuppressive cytokines such as IL6 and IL8, which are correlated with poor prognoses. T cell infiltration in tumors is fewer in OCCC than that in serous ovarian cancers. We screened drug libraries and found twelve chemical compounds capable of inhibiting production of IL6 by OCCC cell lines. One of them epigenetically suppressed HNF-1β, an OCCC-specific transcriptional factor which we previously identified as the upstream for the high production of IL6 and IL8 from OCCC. Some of them also showed reversal of the immunosuppressive conditions in mice implanted with human OCCC cell lines. These results indicate that inhibitors on the HNF-1β-IL6/IL8 pathway may improve immunosuppressive conditions of OCCC and useful for combination immunotherapy for patients with OCCC.

Research Products

• [Journal Article] International validation of the consensus Immunoscore for the prognostic classification of colon cancer (2018)
  • Author(s): Franck Pages, Tomonobu Fujita(98人中74番目), Yutaka Kawakami(93番目),
  • Journal Title: Lancet Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer (2018)
  • Author(s): Tatsuo Matsuda, Hiroya Takeuchi, Toshiharu Sakurai, Shuhei Mayanagi, Eisuke Booka, Tomonobu Fujita, Hajime Higuchi, Junichi Taguchi, Yasuo Hamamoto, Hiromasa Takaishi, Hirofumi Kawakubo, Masato Okamoto, Makoto Sunamura, Yutaka Kawakami, Yuko Kitagawa.
  • Journal Title: Oncology letters Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma (2017)
  • Author(s): Kinoshita T, Kudo-Saito C, Muramatsu R, Fujita T, Saito M, Nagumo H, Sakurai T, Noji S, Takahata E, Yaguchi T, Tsukamoto N, Hayashi Y, Kaseda K, Kamiyama I, Ohtsuka T, Tomizawa K, Shimoji M, Mitsudomi T, Asamura H, Kawakami Y.
  • Journal Title: European Journal of Cancer Volume: 86 Pages: 15-27
  • DOI: 10.1016/j.ejca.2017.08.026
  • Peer Reviewed / Open Access
• [Journal Article] Peptide-pulsed dendritic cell vaccine in combination with carboplatin and paclitaxel chemotherapy for stage IV melanoma. (2017)
  • Author(s): Fukuda K, Funakoshi T, Sakurai T, Nakamura Y, Mori M, Tanese K, Tanikawa A, Taguchi J, Fujita T, Okamoto M, Amagai M, Kawakami Y.
  • Journal Title: Melanoma Research. Volume: in press Issue: 4 Pages: 326-334
  • DOI: 10.1097/cmr.0000000000000342
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer. (2017)
  • Author(s): Shindo Y, Hazama S, Suzuki N, Iguchi H, Uesugi K, Tanaka H, Aruga A, Hatori T, Ishizaki H, Umeda Y, Fujiwara T, Ikemoto T, Shimada M, Yoshimatsu K, Takenouchi H, Matsui H, Kanekiyo S, Iida M, Koki Y, Arima H, Furukawa H, Ueno T, Yoshino S, Fujita T, Kawakami Y, Nakamura Y, Oka M, Nagano H.
  • Journal Title: J Exp Clin Cancer Res. Volume: 36 Issue: 1 Pages: 36-36
  • DOI: 10.1186/s13046-017-0509-1
  • Peer Reviewed / Open Access
• [Journal Article] Progression of Human Renal Cell Carcinoma via Inhibition of RhoA-ROCK Axis by PARG1. (2017)
  • Author(s): Miyazaki J, Ito K, Fujita T, Matsuzaki Y, Asano T, Hayakawa M, Asano T, Kawakami Y.
  • Journal Title: Transl Oncol. Volume: 10 Issue: 2 Pages: 142-152
  • DOI: 10.1016/j.tranon.2016.12.004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer. (2016)
  • Author(s): Kinoshita T, Muramatsu R, Fujita T, Nagumo H, Sakurai T, Noji S, Takahata E, Yaguchi T, Tsukamoto N, Kudo-Saito C, Hayashi Y, Kamiyama I, Ohtsuka T, Asamura H, Kawakami Y.
  • Journal Title: Ann Oncol. Volume: 27 Issue: 11 Pages: 2117-2123
  • DOI: 10.1093/annonc/mdw319
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer. (2015)
  • Author(s): Mayanagi S, Kitago M, Sakurai T, Matsuda T, Fujita T, Higuchi H, Taguchi J, Takeuchi H, Itano O, Aiura K, Hamamoto Y, Takaishi H, Okamoto M, Sunamura M, Kawakami Y, Kitagawa Y.
  • Journal Title: Cancer Science Volume: 106 Issue: 4 Pages: 397-406
  • DOI: 10.1111/cas.12621
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aberrant Myosin 1b Expression Promotes Cell Migration and Lymph Node Metastasis of HNSCC.Mol (2014)
  • Author(s): Ohmura G, Tsujikawa T, Yaguchi T, Kawamura N, Mikami S, Sugiyama J, Nakamura K, Kobayashi A, Iwata T, Nakano H, Shimada T, Hisa Y, Kawakami Y.
  • Journal Title: Cancer Res. Epub ahead of print Volume: 13 Issue: 4 Pages: 721-731
  • DOI: 10.1158/1541-7786.mcr-14-0410
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 悪性黒色腫に対する腫瘍浸潤リンパ球(TIL)輸注療法のfeasibility試 (2017)
  • Author(s): 舩越 建、平井 郁子、神宿 元、中村 善雄、藤田知信、天谷 雅行、河上 裕
  • Organizer: 第33回日本皮膚悪性腫瘍学会学術大会
• [Presentation] Immunobiology and immunotherapy for gynecological cancers (2017)
  • Author(s): Yutaka Kawakami, Tomonori Yaguchi, Taeko Hayakwa, Kinya Tsubota, Juri Sugiyama, Takashi Nishio, Taku Iwata, Tomonobu Fujita, Daisuke Aoki.
  • Organizer: The 5thBiennial Meeting of Asian Society of Gynecologic Oncology
  • Invited
• [Presentation] B-cell subsets possess different roles in colorectal cancer immune-microenvironment. (2017)
  • Author(s): Budiman Kharma, Boryana Popivanova, Tomonobu Fujita, Shuji Mikami Shoichi Hazama, Kiyotaka Okuno, Ryo Matoba, Ichiro Takemasa, Shin Takahashi, Kota Ouchi, Chikashi Ichioka, Yutaka Kawakami.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 癌微小環境における免疫回避抑制機構とその克服法 (2017)
  • Author(s): 谷口智憲、藤田知信、河上裕
  • Organizer: 第26回日本がん転移学会学術集会・総会
  • Invited
• [Presentation] B-cell subsets possess different roles in colorectal cancer immune-microenvironment. (2017)
  • Author(s): Budiman Kharma, Boryana Popivanova, Tomonobu Fujita, Hayashi Yuichiro, Mikami Shuji, suzuki Nobuoki, Nagano Hiroaki, Hazama Shoichi, Okuno Kiyotaka, Matoba Ryo, Takemasa Ichiro, Takahashi Shin Ouchi Kota, Ishioka Chikashi, Kawakami Yutaka.
  • Organizer: 第21回日本がん免疫学会総会
• [Presentation] Immunomodulation of ovarian clear cell carcinoma by targeting HNF-1β-NH-kB-IL6 pathway enhances anti-tumor immunity. (2017)
  • Author(s): Kagawa Masaki, Yaguchi Tomonori, Morii Kenji, Takise Yoshiaki, Nishio Hiroshi, Sugiyama Juri, Iwata Takashi, Fujita Tomonobu, Kawakami Yutaka
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] IL-8 has a negative role on tumor infiltrating CD8+T cells in various cancers. (2017)
  • Author(s): Sayem Mohammad A, Yaguchi Tomonori, Noji Shinobu, Iwata Takashi, Fujita Tomonobu, Kawakami Yutaka.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] 症例ごとの免疫状態評価に基づいた個別化がん免疫療法 (2016)
  • Author(s): 河上裕、藤田知信、谷口智憲
  • 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）
  • Invited
• [Presentation] がん免疫療法の血液バイオマーカー (2016)
  • Author(s): 藤田知信、野路しのぶ、南雲春菜、岡本正人、桜井敏晴、中面哲也、松枝智子、伊東恭悟、竹之内寛子、硲彰一、岡正朗、河上裕
  • 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）
  • Invited
• [Presentation] Identification of biomarkers for immune-checkpoint blockade (2016)
  • Author(s): 河上裕、木下智成、Boryana Popivanova, Sunthamala Nuchsupha, Mohammad Abu Sayem, 杉山重里、西尾浩、谷口智憲、藤田知信
  • 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）
  • Invited
• [Presentation] がんワクチン後の予後を予測する血液バイオマーカーの道程とその制御 (2015)
  • Author(s): 藤田知信、野路しのぶ、南雲春菜、早川妙香、西尾浩、杉山重里、坪田欣也、中村謙太、岡本正人、桜井敏晴、松枝智子、伊東恭悟、竹之内寛子、硲彰一、岡正朗、谷口智憲、河上裕
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-10-22
• [Presentation] Differential prognostic roles of tumor infiltrating lymphocyte in patients with resected non-small cell lung cancer (2015)
  • Author(s): Kinoshita Tomonari, Fujita Tomonobu, Muramatsu Reiko, Hayashi Yuichiro, Noji Shinobu, Sakura Toshiharu, Asamura Hisao, Kawakami Yutaka
  • Organizer: ICCIM2015 (19th JACI & 23rd MMCB)
  • Place of Presentation: 東京大学伊藤国際学術センター内伊藤謝恩ホール（東京都文京区）
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [Book] 実験医学増刊 がん免疫療法 (2016)
  • Author(s): 河上裕、藤田知信
  • Total Pages: 7
  • Publisher: 羊土社