Clarifying the significance of Notch signal activation in B-cell lymphomas

• Project/Area Number: 18K08324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto University
• Principal Investigator: Nishikori Momoko 京都大学, 医学研究科, 講師 (60378635)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 悪性リンパ腫 / 免疫微小環境 / 免疫逃避機構 / B細胞リンパ腫 / 腫瘍微小環境 / T細胞 / Notch

Outline of Final Research Achievements

Activating mutations of Notch 1 and 2 are often found in B-cell lymphomas. We found that B cells with constitutive Notch1 activation preferentially induce T-cell responses that does not involve in the anti-lymphoma immune reaction (type2 helper T-cell and regulatory T-cells) via IL33 production. On the other hand, loss of CD58 is a common mechanism for tumor immune evasion in lymphoid malignancies. We performed epigenetic library screening and found that EZH2 inhibitors specifically enhanced CD58 expression of lymphoma cells. Restoring the expression of CD58 in lymphoma cells using an EZH2 inhibitor was shown to enhance immune reaction of T and NK cells against lymphoma cells. These findings provide a molecular basis for immunotherapy for lymphoma treatment.

Academic Significance and Societal Importance of the Research Achievements

本研究ではB細胞リンパ腫における免疫逃避機構を明らかにし、その治療応用を行うことを目指した。我々はB細胞リンパ腫にしばしば認められるNotchシグナルの活性化異常が抗腫瘍免疫の作用しにくいT細胞反応をもたらすことを明らかにした。また、遺伝子発現修飾機構（エピゲノム修飾）により低下したリンパ腫のCD58の発現をEZH2阻害薬が回復させることにより、リンパ腫に対する免疫を活性化することができることを示した。

Research Products

• [Journal Article] Epigenetic suppression of SLFN11 in germinal center B-cells during B-cell development (2021)
  • Author(s): Moribe F, Nishikori M, Takashima T, Taniyama D, Onishi N, Arima H, Sasanuma H, Akagawa R, Elloumi F, Takeda S, Pommier Y, Morii E, Takaori-Kondo A, Murai J.
  • Journal Title: PLoS One. Volume: 16 Issue: 1 Pages: 0237554-0237554
  • DOI: 10.1371/journal.pone.0237554
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells (2020)
  • Author(s): Jo Tomoyasu、Nishikori Momoko、Kogure Yasunori、Arima Hiroshi、Sasaki Katsuhiro、Sasaki Yoshiteru、Nakagawa Tomoko、Iwai Fumie、Momose Shuji、Shiraishi Aki、Kiyonari Hiroshi、Kagaya Noritaka、Onuki Tetsuo、Shin-ya Kazuo、Yoshida Minoru、Kataoka Keisuke、Ogawa Seishi、Iwai Kazuhiro、Takaori-Kondo Akifumi
  • Journal Title: Blood Volume: 136 Issue: 6 Pages: 684-697
  • DOI: 10.1182/blood.2019002654
  • Peer Reviewed / Open Access
• [Journal Article] EZH2 inhibitors restore epigenetically silenced CD58 expression in B cell lymphomas (2020)
  • Author(s): Yasuyuki Otsuka, Momoko Nishikori, Hiroshi Arima, Kiyotaka Izumi, Toshio Kitawaki, Masakatsu Hishizawa Akifumi Takaori-Kondo
  • Journal Title: Molecular Immunology Volume: 119 Pages: 35-45
  • DOI: 10.1016/j.molimm.2020.01.006
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and characterization of a MALT lymphoma cell line carrying an API2‐MALT1 translocation (2020)
  • Author(s): Izumi Kiyotaka、Nishikori Momoko、Yuan Hepei、Otsuka Yasuyuki、Nakao Kensuke、Takaori‐Kondo Akifumi
  • Journal Title: Genes, Chromosomes and Cancer Volume: 59 Issue: 9 Pages: 517-524
  • DOI: 10.1002/gcc.22855
  • Peer Reviewed / Open Access
• [Journal Article] Secondary failure of platelet recovery in patients treated with high-dose thiotepa and busulfan followed by autologous stem cell transplantation (2020)
  • Author(s): Wada Fumiya、Nishikori Momoko、Hishizawa Masakatsu、Watanabe Mitsumasa、Aiba Akiko、Kitano Toshiyuki、Shimazu Yayoi、Shindo Takero、Kondo Tadakazu、Takaori-Kondo Akifumi
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 5 Pages: 609-613
  • DOI: 10.1007/s12185-020-03007-4
  • Peer Reviewed / Open Access
• [Journal Article] Histologic transformation of t(11;18)-positive MALT lymphoma presented with aberrant T-cell marker expression (2020)
  • Author(s): Naoki Tamura, Hirona Maeda, Momoko Nishikori, Haruyuki Fujita, Masakatsu Hishizawa, Hironori Haga, Akifumi Takaori-Kondo
  • Journal Title: International Journal of Hematology Volume: - Issue: 5 Pages: 724-732
  • DOI: 10.1007/s12185-019-02810-y
  • Peer Reviewed / Open Access
• [Journal Article] SLAM family member 8 is expressed in and enhances the growth of anaplastic large cell lymphoma. (2020)
  • Author(s): Sugimoto A, Kataoka TR, Ito H, Kitamura K, Saito N, Hirata M, Ueshima C, Takei Y, Moriyoshi K, Otsuka Y, Nishikori M, Takaori-Kondo A, Haga H.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1 Pages: 2505-2505
  • DOI: 10.1038/s41598-020-59530-1
  • NAID: 120006895429
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent Epstein-Barr Virus-positive (EBV+) Primary Central Nervous System Lymphoma (PCNSL) in a Patient with Clinical Features of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) (2019)
  • Author(s): Nagano Masahiro、Ayaki Takashi、Koita Natsuko、Kitano Toshiyuki、Nishikori Momoko、Goda Naoki、Minamiguchi Sachiko、Ikeda Akio、Takaori-Kondo Akifumi、Takahashi Ryosuke
  • Journal Title: Internal Medicine Volume: 58 Issue: 6 Pages: 849-854
  • DOI: 10.2169/internalmedicine.1246-18
  • NAID: 130007611374
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-03-15
  • Peer Reviewed / Open Access
• [Journal Article] Outcomes of allogeneic stem cell transplantation for DLBCL: a multi-center study from the Kyoto Stem Cell Transplantation Group. (2019)
  • Author(s): Kiyotaka Izumi, Junya Kanda, Momoko Nishikori, et al.
  • Journal Title: Annals of Hematology Volume: 98 Issue: 12 Pages: 2815-2823
  • DOI: 10.1007/s00277-019-03835-3
  • Peer Reviewed
• [Journal Article] Pharmacokinetics of thiotepa in high-dose regimens for autologous hematopoietic stem cell transplant in Japanese patients with pediatric tumors or adult lymphoma (2019)
  • Author(s): Kondo, E., Ikeda, T., Goto, H. Nishikori M et al.
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: 84 Issue: 4 Pages: 849-860
  • DOI: 10.1007/s00280-019-03914-2
  • Peer Reviewed
• [Journal Article] Effectiveness of cord blood transplantation for the treatment of refractory angioimmunoblastic T-cell lymphoma: a series of three cases (2019)
  • Author(s): Kazuma Yasuhiro、Shimazu Yayoi、Hishizawa Masakatsu、Nishikori Momoko、Kitano Toshiyuki、Kondo Tadakazu、Yamashita Kouhei、Takaori-Kondo Akifumi
  • Journal Title: Bone Marrow Transplantation Volume: - Issue: 10 Pages: 1710-1712
  • DOI: 10.1038/s41409-019-0494-4
  • Peer Reviewed / Open Access
• [Journal Article] B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell?dominant T-cell responses via IL-33 (2018)
  • Author(s): Arima Hiroshi、Nishikori Momoko、Otsuka Yasuyuki、Kishimoto Wataru、Izumi Kiyotaka、Yasuda Koubun、Yoshimoto Tomohiro、Takaori-Kondo Akifumi
  • Journal Title: Blood Advances Volume: 2 Issue: 18 Pages: 2282-2295
  • DOI: 10.1182/bloodadvances.2018019919
  • Peer Reviewed / Open Access
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for 8p11 myeloproliferative syndrome with BCR-FGFR1 gene rearrangement: a case report and literature review (2018)
  • Author(s): Konishi Yoshinobu、Kondo Tadakazu、Nakao Kensuke、Asagoe Kohusuke、Otsuka Yasuyuki、Nishikori Momoko、Hishizawa Masakatsu、Yamashita Kouhei、Takaori-Kondo Akifumi
  • Journal Title: Bone Marrow Transplantation Volume: 54 Issue: 2 Pages: 326-329
  • DOI: 10.1038/s41409-018-0287-1
  • Peer Reviewed / Open Access
• [Presentation] EZH2 inhibitors restore epigenetically silenced CD58 expression of B-cell lymphomas (2019)
  • Author(s): 大塚泰幸、錦織桃子、有馬浩史、袁和培、髙折晃史
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] EZH2 inhibitor enhances T-cell migration to B-cell lymphoma by upregulating CCL17 expression． (2019)
  • Author(s): 袁和培、錦織桃子、大塚泰幸、有馬浩史、北脇年雄、高折晃史
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] API2-MALT1融合遺伝子を有するMALTリンパ腫由来細胞株の樹立 (2019)
  • Author(s): 和泉清隆、大塚泰幸、藤田晴之、有馬浩史、錦織桃子、高折晃史
  • Organizer: 第59回 日本リンパ網内系学会総会
• [Presentation] B Cells with Aberrant Activation of Notch1 Signaling Promote Treg and Th2 Cell-Dominant T Cell Responses via IL-33． (2018)
  • Author(s): ＊有馬浩史、錦織桃子、大塚泰幸、和泉清隆、岸本渉、髙折晃史．
  • Organizer: The 9th JSH International Symposium
  • Int'l Joint Research
• [Presentation] 後天性血管性浮腫を合併した難治性脾辺縁帯リンパ腫に対しベンダムスチン・リツキシマブ(BR)療法が奏効した一例． (2018)
  • Author(s): 大塚泰幸、錦織桃子、髙折晃史．
  • Organizer: 第58回日本リンパ網内系学会総会
• [Presentation] 免疫逃避機構を標的とした悪性リンパ腫治療の可能性． (2018)
  • Author(s): 錦織桃子、大塚泰幸、髙折晃史．
  • Organizer: 第58回日本リンパ網内系学会総会
  • Invited
• [Presentation] Notch signaling activation parallels IL33 expression and Treg cell-rich signatures in DLBCL. (2018)
  • Author(s): ＊有馬浩史、錦織桃子、大塚泰幸、和泉清隆、岸本渉、髙折晃史．
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Mechanisms underlying augmented lymphomagenesis by LUBAC; Possible accumulation of AID-mediated somatic mutations. (2018)
  • Author(s): ＊Tomoyasu Jo, Momoko Nishikori, Yoshiteru Sasaki, Yasunori Kogure, Keisuke Kataoka, Seishi Ogawa, Kazuhiro Iwai, and Akifumi Takaori-Kondo.
  • Organizer: The 60th ASH Annual Meeting,
  • Int'l Joint Research