Analysis of B cell receptors expressed on tumor infiltrating B cells by next generation sequencing

• Project/Area Number: 15K14410
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Juntendo University
• Principal Investigator: TAKEDA KAZUYOSHI 順天堂大学, 医学(系)研究科(研究院), 准教授 (80272821)
• Co-Investigator(Renkei-kenkyūsha): SUZUKI Ryuji 独立行政法人国立病院機構(相模原病院臨床研究センター), 診断・治療研究室, 室長 (70373470)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: B細胞レセプター / 抗体 / T細胞レセプター / 抗腫瘍抗体 / 腫瘍免疫 / 次世代型シークエンサー / 次世代シークエンサー

Outline of Final Research Achievements

We have examined B cell receptor (BCR)(antibody) expressed on tumor infiltrating B cells (BCRs) by next generation sequencing (NGS).In the tumors that were effectively rejected by immune therapies, BCR clonality was less. Besides, BCRs were highly oligoclonal when we examined TIBs in the immune therapy-resistant tumors, suggesting specific infiltration of TIBs. We now analyze whether alteration of BCR clonality is causes or results of the difference of therapeutic effects. Moreover, we made antibodies produced by TIBs that clonaly infiltrating in resistant tumors and antibodies produced by TIBs commonly observed in several rejected tumors, and we are now going to define their antigens.

Research Products

• [Int'l Joint Research] Garvan Institute of Medical Research/QIMR Berghofer Medical Research Inst./University of Queensland(Australia)
• [Int'l Joint Research] Icahn School of Medicine at Mount Sinai(USA)
• [Int'l Joint Research] QIMR Berghofer/Medical Research Institute(Australia)
• [Int'l Joint Research] School of Medicine/University of Queensland(Australia)
• [Int'l Joint Research] Washington University, St. Louis, MO/St. Louis, MO(USA)
• [Journal Article] Effective induction of cytotoxic T cells recognizing an epitope peptide derived from hypoxia-inducible protein 2 (HIG2) in patients with metastatic renal cell carcinoma. (2017)
  • Author(s): Obara, W., Karashima, T., Takeda, K., Kato, R., Kato, Y., Kanehira, M., Takata, R., Inoue, K., Katagiri, T., Shuin, T., Nakamura, Y. & Fujioka, T.
  • Journal Title: Cancer Immunol. Immunother. Volume: 66 Pages: 17-24
  • DOI: 10.1007/s00262-016-1915-5
  • Peer Reviewed
• [Journal Article] IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting (2017)
  • Author(s): Takeda K, Nakayama M, Hayakawa Y, Kojima Y, Ikeda H, Imai N, Ogasawara K, Okumura K, Thomas DM, Smyth MJ
  • Journal Title: Nature Communications Volume: 8 Pages: 14607-14607
  • DOI: 10.1038/ncomms14607
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis. (2017)
  • Author(s): Putz, E. M., Guillerey, C., Kos, K., Stannard, K., Miles, K., Delconte, R. B., Takeda, K., Nicholson, S. E., Huntington, N. D. 6 Smyth, M. J.
  • Journal Title: Oncoimmunology Volume: 6
  • DOI: 10.1080/2162402x.2016.1267892
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Suppression of metastasis using a new lymphocyte checkpoint target for cancer immunotherapy. (2016)
  • Author(s): Blake, S. J., Stannard, K., Liu, J., Allen, S., Yong, M. C., Mittal, D., Aguilera, A. R., Miles, J. J., Lutzky, V. P., de Andrade, L. F., Martinet, L., Colonna, M., Takeda, K., Kuhnel, F., Gurlevik, E., Bernhardt, G., Teng, M. W., & Smyth, M. J.
  • Journal Title: Cancer Discov. Volume: 6 Pages: 446-459
  • DOI: 10.1158/2159-8290.cd-15-0944
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phase I clinical trial of a five-peptide cancer vaccine combined with cyclophosphamide in advanced solid tumors (2016)
  • Author(s): Murahashi, M., Hijikata, Y., Yamada, K., Tanaka, Y., Kishimoto, J., Inoue, H., Marumoto, T., Takahazhi, A., Okazaki, T., Takeda, K., Hirakawa, M., Fujii, H., Okano, S., Morita, M., Baba, E., Mizumoto, K., Maehara, Y., Tanaka, M., Akashi, K., Nakanishi, Y., Yoshida, K., Tsunoda, T., Tamura, K., Nakamura, Y., & Tani, K.
  • Journal Title: Clin. Immunol. Volume: 166-167 Pages: 48-58
  • DOI: 10.1016/j.clim.2016.03.015
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. (2016)
  • Author(s): Young, A., Ngiow, S. F., Barkauskas, D. S., Sult, E., Hay, C., Stephen J. Blake, S. J., Huang, Q., Liu, J., Takeda, K., Teng, M. W. L., Sachsenmeier, K., & Smyth, M. J.
  • Journal Title: Cancer Cell Volume: 30 Pages: 391-403
  • DOI: 10.1016/j.ccell.2016.06.025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Assessing immune-related adverse events of efficacious combination immunotherapies in preclinical models of cancer. (2016)
  • Author(s): Liu, J., Blake, S. J., Harjunpaa, H., Fairfax, K. A., Yong, M. C., Allen, S., Kohrt, H. E., Takeda, K., Smyth, M. J., & Teng, M. W. L.
  • Journal Title: Cancer Res. Volume: 76 Pages: 5288-5301
  • DOI: 10.1158/0008-5472.can-16-0194
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. (2016)
  • Author(s): Liu, J., Blake, S. J., Yong, M. C., Harjunpaa, H., Ngiow, S. F., Takeda, K., Young, A., O’Donell, J. S., Allen, S., Smyth, M.J., & Teng, M. W. L.
  • Journal Title: Cancer Discov. Volume: 6 Pages: 1382-1399
  • DOI: 10.1158/2159-8290.cd-16-0577
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Agonists of the TRAIL death receptor DR5 sensitize intestinal stem cells to chemotherapy-induced cell death and trigger gastrointestinal toxicity. (2016)
  • Author(s): Finnberg, N. K., Gokare, P., Navaraj, A., Lang Luhs K. A., Cerniglia, G., Yagita, H., Takeda, K., Motoyama, N., and EL-Deiry, W. S.
  • Journal Title: Cancer Res Volume: 76 Pages: 700-712
  • DOI: 10.1158/0008-5472.can-15-2759
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NK cells require IL-28R for optimal in vivo activity. (2015)
  • Author(s): Souza-Fonseca-Guimaraes, F., Young, A., Mittal, D., Martinet, L., Bruedigam, C., Takeda, K., Degli-Esposti, M., Andoniou, C. E., Hill, G. R. and Smyth, M.J.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 112
  • DOI: 10.1073/pnas.1424241112
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High-dose cyclophosphamide induces specific tumor immunity with conccomitant recruitment of LAMP1/CD107a-expressing CD4-positive T cells into tumor sites (2015)
  • Author(s): Naito, T., Baba, T., Takeda, K., Sasaki, S., Nakamoto, Y. and Mukaida, N.
  • Journal Title: Cancer Lett Volume: 366 Pages: 93-99
  • DOI: 10.1016/j.canlet.2015.06.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Toll-Like Receptor 3 regulates NK cell responses to cytokines and controls experimental metastasis. (2015)
  • Author(s): Guillerey, C., Chow, M. T., Miles, K., Olver, S., Sceneay, J., Takeda, K., Mollere, A. and Smyth, M.J.
  • Journal Title: OncoImmunology Volume: 4
  • DOI: 10.1080/2162402x.2015.1027468
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Interferon-γ-Mediated Natural Killer Cell Activation by an Aqueous Panax ginseng Extract. (2015)
  • Author(s): Takeda, K. and Okumura, K.
  • Journal Title: eCAM Volume: 2015 Pages: 1-11
  • DOI: 10.1155/2015/603198
  • Peer Reviewed / Open Access
• [Presentation] Most of the CD8+ TIL are tumor reactive in spontaneously regressing or progressing murine gastric cancer (2015)
  • Author(s): Nagaoka, K., Hosoi, A., Matsushita, H., Kubo, M., Takeda, K., Kakimi, K.
  • Organizer: 第44回日本免疫学会学術総会
  • Place of Presentation: 北海道札幌市
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] Carcinoma-associated fibroblasts raise highly aggressive cancer cells via metastasis-promoting autocrine signaling (2015)
  • Author(s): Matsumura, Y., Ito, Y., Wali, N., Ito, T, Mogushi, K., Terao, Y., Takeda, S., Okumura, K., Takeda, K., Hino, O., Orimo, A.
  • 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
  • Int'l Joint Research
• [Presentation] IFN-γ produced by cytotoxic T cells immunoedits the cancer genome (2015)
  • Author(s): Takeda, K.
  • Organizer: International conference of cancer immunotherapy and macrophage 2015
  • Place of Presentation: 東京都文京区
  • Year and Date: 2015-07-09
  • Int'l Joint Research