Analysis of differentiation mechanism of peripherally induced Foxp3 positive T cells for application to cancer treatment

• Project/Area Number: 23501284
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor immunology
• Research Institution: Mie University
• Principal Investigator: MIYAHARA Yoshihiro 三重大学, 医学(系)研究科(研究院), 講師 (10582083)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 免疫抑制 / 腫瘍免疫

Research Abstract

We have previously established a 2-step culture method for differentiating Foxp3- naive CD4+ T cells to Foxp3+ induced-regulatory T cells (iTregs). Firstly, we stimulate naive CD4+ T cells by anti-CD3 mAb and anti-CD28 mAb in the presence of Jak3 inhibitor for 3 days (conditioning stage). Secondary, we keep culturing Foxp3- iTregs precursor T cells to differentiate these cells to Foxp3+ iTregs in the presence of IL-2 for 3 days (differentiation stage). We analyzed what kind of factors could affect this protocol. In this study, we have identified that IL-2 signaling pathway was the main target of Jak3 inhibitor, and IL-4 was the strongest inhibiting cytokine in the differentiation stage from Foxp3- iTregs precursor cells to Foxp3+ iTregs. We also confirmed that STAT6, a downstream molecule of IL-4 signaling pathway, was an important molecule. These results obtained in this study are important for developing effective cancer treatment by regulating the differentiation into iTregs.

Research Products

• [Journal Article] Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions (2014)
  • Author(s): Khattar M, Miyahara Y, Schroder PM, Xie A, Chen W, Stepkowski SM
  • Journal Title: PLoS One Volume: 9(1)
  • Peer Reviewed
• [Journal Article] Dose-dependent effects of NY-ESO-1 protein vaccine complexed with cholesteryl pullulan (CHP-NY-ESO-1) on immune responses and survival benefits of esophageal cancer patients (2013)
  • Author(s): Kageyama S, Wada H, Muro K, Niwa Y, Ueda S, Miyata H, Takiguchi S, Sugino SH, Miyahara Y, Ikeda H, Imai N, Sato E, Yamada T, Osako M, Ohnishi M, Harada N, Hishida T, Doki Y, Shiku H
  • Journal Title: J Transl Med Volume: 11 Pages: 246-246
  • Peer Reviewed
• [Journal Article] A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells (2013)
  • Author(s): Guo Z, Khattar M, Schroder PM, Miyahara Y, Wang G, He X, Chen W, Stepkowski SM
  • Journal Title: J Immunol Volume: 190(7) Pages: 3153-3162
  • Peer Reviewed
• [Journal Article] Dose-dependent effects of NY-ESO-1 protein vaccine complexed with cholesteryl pullulan (CHP-NY-ESO-1) on immune responses and survival benefits of esophageal cancer patients (2013)
  • Author(s): Kageyama S, Wada H, Muro K, Niwa Y, Ueda S, Miyata H, Takiguchi S, Sugino SH, Miyahara Y, Ikeda H, Imai N, Sato E, Yamada T, Osako M, Ohnishi M, Harada N, Hishida T, Doki Y, Shiku H
  • Journal Title: Journal of translational medicine Volume: 5;11 Issue: 1 Pages: 246-246
  • DOI: 10.1186/1479-5876-11-246
  • Peer Reviewed
• [Journal Article] A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells (2013)
  • Author(s): Guo Z, Khattar M, Schroder PM, Miyahara Y, Wang G, He X, Chen W, Stepkowski SM
  • Journal Title: Journal of immunology Volume: 190(7) Issue: 7 Pages: 3153-3162
  • DOI: 10.4049/jimmunol.1200751
  • Peer Reviewed
• [Journal Article] siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T-cell effector functions (2012)
  • Author(s): Iwamura K, Kato T, Miyahara Y, Naota H, Mineno J, Ikeda H, Shiku H
  • Journal Title: Gene Ther Volume: 19(10) Pages: 959-966
  • Peer Reviewed
• [Journal Article] Anti-TCRβ mAb induces long-term allograft survival by reducing antigen-reactive T cells and sparing regulatory T cells (2012)
  • Author(s): Miyahara Y, Khattar M, Schroder PM, Mierzejewska B, Deng R, Han R, Hancock WW, Chen W, Stepkowski SM
  • Journal Title: Am J Transplant Volume: 12(6) Pages: 1409-1418
  • Peer Reviewed
• [Journal Article] anti-TCRβ mAb Induces Long-Term Allograft Survival by Reducing Antigen-Reactive T Cells and Sparing Regulatory T Cells (2012)
  • Author(s): Y. Miyahara, M. Khattar, P. M. Schroder, B. Mierzejewska, R. Deng, R. Han, W. W. Hancock, W. Chen, S. M. Stepkowski
  • Journal Title: American Journal of Transplantation Volume: 12(6) Issue: 6 Pages: 1409-1418
  • DOI: 10.1111/j.1600-6143.2012.04006.x
  • Peer Reviewed
• [Journal Article] H.Intratumoral injection of Propionibacterium acnes suppresses malignant melanoma by enhancing Th1 immune responses (2011)
  • Author(s): Tsuda K, Yamanaka K, Linan W, Miyahara Y, Akeda T, Nakanishi T, Kitagawa H, Kakeda M, Kurokawa I, Shiku H, Gabazza EC, Mizutani
  • Journal Title: PLoS One Volume: 6(12)
  • Peer Reviewed
• [Journal Article] Intratumoral injection of Propionibacterium acnes suppresses malignant melanoma by enhancing Th1 immune responses (2011)
  • Author(s): K Tsuda, K Yamanaka, W ang L,Y Miyahara, T Akeda, T Nakanishi, H Kitagawa, M Kakeda, I Kurokawa, H Shiku, E C. Gabazza, and H Mizutani
  • Journal Title: PLoS One Volume: 6(12) Issue: 12 Pages: e29020-e29020
  • DOI: 10.1371/journal.pone.0029020
  • Peer Reviewed
• [Presentation] Adoptive transfer of wild-type TCR-gene transduced T lymphocytes targeting MAGE-A4 antigen to patients with refractory esophageal cancer (2014)
  • Author(s): S Kageyama, H Ikeda, N Imai, M Ishihara, Y Miyahara, S Ueda, T Ishikawa, H Naota, K Ohishi, T Shiraishi, N Inoue, M Tanabe, T Kidokoro, H Yoshioka, D Tomura, I Nukaya, J Mineno, K Takesako, N Katayama, H Shiku
  • Organizer: American Assosication for Cancer Research Annual meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-05
• [Presentation] Adoptive transfer of TCR gene-transduced lymphocytes targeting MAGE-A4 for refractory esophageal cancer (2014)
  • Author(s): Y Miyahara, S Kageyama, H Ikeda, M Ishihara, N Katayama, D Tomura, I Nukaya, J Mineno, K Takesako, H Shiku
  • Organizer: ITOC-1 Immunotherapy of Cancer Conference
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-03-12
• [Presentation] Adoptive transfer of TCR gene-transduced lymphocytes targeting MAGE-A4 for refractory esophageal cancer (2014)
  • Author(s): Yoshihiro Miyahara, Shinichi Kageyama, Hiroaki Ikeda, Mikiya Ishihara, Naoyuki Katayama, Daisuke Tomura, Ikuei Nukaya, Junichi Mineno, Kazuto Takesako, Hiroshi Shiku
  • Organizer: ITOC-1 Immunotherapy of Cancer Conference
  • Place of Presentation: ミュンヘン ドイツ
• [Presentation] 化療・放射線療法後、胃全摘、膵尾部切除、脾摘、右腎摘、横行結腸部分切除、脳転移2回、肺転移で活性化リンパ輸注療法を続けているQOL 良好な長期生存例 (2013)
  • Author(s): 片平智行、坂本英至、関行雄、三村三喜男、吉岡洋、都築豊徳、二村舞子、金田次弘、宮原慶裕、珠玖洋
  • Place of Presentation: 盛岡
  • Year and Date: 2013-12-05
• [Presentation] (2013)
  • Author(s): H Ikeda, S Kageyama, N Imai, Y Miyahara, M Ishihara, N Katayama, H Yoshioka, D Tomura, I Nukaya, J Mineno, K Takesako, H Shiku
  • Organizer: 28^<th> Annual Meeting of Society for Immunotherapy of Cancer
  • Place of Presentation: National Harbor, MD, USA
  • Year and Date: 2013-11-07
• [Presentation] HLA-A0206+NY-ESO-1+tumor cell lines can be recognized by HLA-A0201 restricted-NY-ESO-1(p157-165) specific TCRs (2013)
  • Author(s): 宮原慶裕、杉野早穂子、王立楠、葛島清隆、藤田知信、河上裕、岡本幸子、天石泰典、峰野純一、珠玖洋
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03
• [Presentation] MAGE-A4 発現食道癌における抗原特異的 TCR 遺伝子導入リンパ球輸注後の in vivo 血中持続 (2013)
  • Author(s): 影山慎一、池田裕明、今井奈緒子、上田修吾、石川剛、直田浩明、宮原慶裕、吉岡広文、戸村大助、糠谷育衛、峰野純一、片山直之、珠玖洋
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03
• [Presentation] MAGE-A4 特異的 T 細胞受容体を用いた遺伝子免疫治療における免疫モニタリング (2013)
  • Author(s): 杉野早穂子、宮原慶裕、上田修吾、石川剛、古倉聡、池田裕明、影山慎一、糠谷育衛、戸村大助、吉岡広文、峰野純一、珠玖洋
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03
• [Presentation] 進行・再発固形癌に対するCHP-MAGE-A4 がんワクチン療法第 I 相臨床試験 (2013)
  • Author(s): 上田修吾、影山慎一、宮原慶裕、珠玖洋
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03
• [Presentation] Serological analysis of "antigen spreading" induced by cholesteryl pullulan (CHP)-MAGEA4 vaccination (2013)
  • Author(s): 堀早穂子、宮原慶裕、影山慎一、池田裕明、藤田知信、河上裕、上田修吾、宮本正樹、土川貴裕、平野聡、川上和孝、五島直樹、珠玖洋
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2013-09-19
• [Presentation] 食道癌を対象にしたTCR 遺伝子導入リンパ球輸注療法における輸注細胞の血中動態 (2013)
  • Author(s): 影山慎一、池田裕明、宮原慶裕、今井奈緒子、石原幹也、斉藤佳菜子、片山直之、上田修吾、戸村大助、糠谷育衛、峰野純一、竹迫一任、珠玖洋
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2013-09-19
• [Presentation] 子宮平滑筋肉腫長期生存例における活性化リンパ球輸注療法の効果 (2013)
  • Author(s): 片平智行、長谷川正規、金田次弘、二村舞子、原田智子、細井延行、倉内修、藤田興一、青田泰博、宮原慶裕、珠玖洋
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2013-09-19
• [Presentation] 食道癌を対象にしたMAGE-A4 特異的TCR 遺伝子導入リンパ球輸注における輸注細胞の体内動態と臨床評価 (2013)
  • Author(s): 影山慎一、池田裕明、今井奈緒子、石原幹也、斉藤佳菜子、上田修吾、石川剛、古倉聡、直田浩明、宮原慶裕、城所知秀、井上直樹、田辺雅茂、吉岡広文、戸村大助、糠谷育衛、岡本幸子、峰野純一、白石泰三、大石晃嗣、片山直之、珠玖洋
  • Organizer: 第17回日本がん免疫学会総会
  • Place of Presentation: 宇部
  • Year and Date: 2013-07-03
• [Presentation] ANTIGEN RECEPTOR GENE-MODIFIED LYMPHOCYTES : HARNESSING T CELLS FOR EFFECTIVE CANCER TREATMENT WITH NOVEL VECTORS AND MANIPULATIONS (2013)
  • Author(s): H Ikeda, S Kageyama, N Imai, Y Miyahara, M Ishihara, A Kawamura, M Yamane, D Tomura, S Okamoto, I Nukaya, J Mineno, K Takesako, N Katayama, H Shiku
  • Organizer: American Assosication for Cancer Research Annual meeting
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2013-04-05
• [Presentation] HLA-A0206+ NY-ESO-1+ tumor cell lines can be recognized by HLA-A0201 restricted-NY-ESO-1(p157-165) specific TCRs (2013)
  • Author(s): Yoshihiro Miyahara, Sahoko Sugino, Linan Wang, Kiyotaka Kuzushima, Tomonobu Fujita, Yutaka Kawakami, Sachiko Okamoto, Yasunori Amaishi, Junichi Mineno, Hiroshi Shiku
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Immuno-monitoring of adoptive immunotherapy using patient’s autologous T cells redirected by MAGE-A4 specific TCR gene transduction (2013)
  • Author(s): Sahoko Sugino, Yoshihiro Miyahara, Shugo Ueda, Takeshi Ishikawa, Satoshi Kokura, Hiroaki Ikeda, Shinichi Kageyama, Ikuei Nukaya, Daisuke Tomura, Hirofumi Yoshioka, Junichi Mineno, Hiroshi Shiku
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 遺伝子改変T 細胞の臨床応用 (2012)
  • Author(s): 池田裕明、影山慎一、宮原慶裕、今井奈緒子、石原幹也、岡本幸子、糠谷育衛、峰野純一、竹迫一任、珠玖洋
  • Organizer: 第16回日本癌免疫学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-07-26
• [Presentation] 食道癌症例を対象にしたTCR 遺伝子導入リンパ球輸注後の血中細胞動態 (2011)
  • Author(s): 影山慎一、池田裕明、宮原慶裕、堀早穂子、斉藤佳菜子、今井奈緒子、岡本幸子、戸村大助、糠谷育衛、峰野純一、竹迫一任、片山直之、珠玖洋
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] Protein array-based serological analysis of immune responses induced by cholesteryl pullulan (CHP)-MAGEA4 vaccination (2011)
  • Author(s): 宮原慶裕、堀早穂子、山本明美、白倉和子、前田優香、西川博嘉、上田修吾、宮本正樹、川上和孝、五島直樹、村岡大輔、原田直純、藤田知信、河上裕、池田裕明、影山慎一、珠玖洋
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] ヒト腫瘍抗原特異的T 細胞へのPD-L1/PD-L2 siRNA 導入によるT 細胞機能の増強 (2011)
  • Author(s): 岩村康一、加藤琢磨、宮原慶裕、直田浩明、峰野純一郎、池田浩明、竹迫一任、珠玖洋
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] ヒト腫瘍抗原特異的T 細胞へのPD-L1/PD-L2 siRNA 導入によるT 細胞機能の増強 (2011)
  • Author(s): 岩村康一、加藤琢磨、宮原慶裕、直田浩明、峰野純一郎、池田浩明、竹迫一任、珠玖洋
  • Organizer: 第15回日本がん免疫学会総会
  • Place of Presentation: 大阪
• [Presentation] Protein array-based serological analysis of immune responses induced by cholesteryl pullulan (CHP)-MAGEA4 vaccination (2011)
  • Author(s): Y Miyahara, S Hori, A Yamamoto, K Shirakura, Y Maeda, H Nishikawa, S Ueda, et.al.
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] Clinical application of TCR gene-transduced lymphocytes for patients with epitherial cancer and other types of malignancy: In vivo persistence of adoptively transferred TCR gene-transduced lymphocytes with anti-tumor reactivity in patients
  • Author(s): H Ikeda, S Kageyama, N Imai, Y Miyahara, M Ishihara, N Katayama, H Yoshioka, D Tomura, I Nukaya, J Mineno, K Takesako, H Shiku
  • Organizer: 2013 European society of gene & cell therapy (ESGCT) and SETGyC Collaborative Congress
  • Place of Presentation: Madrid, Spain
• [Book] 抗CTLA-4 抗体による免疫制御機構の解除. 臨床免疫・アレルギー科 特集I;腫瘍の免疫回避機構 vol.56 (2011)
  • Author(s): 宮原慶裕、珠玖洋
• [Remarks]
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