Analysis of anti-tumor immune mechanisms involved in the pathogenesis of multiple myeloma

• Project/Area Number: 20K08743
• 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: Kindai University
• Principal Investigator: Tanaka Hirokazu 近畿大学, 医学部, 臨床教授 (40360846)
• Co-Investigator(Kenkyū-buntansha): 松村 到 近畿大学, 医学部, 教授 (00294083) ; 頼 晋也 近畿大学, 医学部, 講師 (70460855) ; 森田 泰慶 近畿大学, 医学部, 准教授 (80411594)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 多発性骨髄腫 / 骨髄微小環境 / 腫瘍免疫 / 幹細胞

Outline of Research at the Start

多発性骨髄腫（MM）の治療奏効や再発等に関わる免疫動態の詳細は、未だ明らかではない。申請者らは、表面抗原で特徴づけられるMM細胞中に、幹細胞活性、治療抵抗性、および免疫回避能を有するclonogenicな細胞が数%存在し、MM幹細胞として機能していることを見出した。本研究では、治療前後の様々な奏効状態にあるMM幹細胞を用いて、その分子遺伝学的特性を明らかにする。また、同時に存在する抗腫瘍免疫担当細胞の特性を解析することで、MMの病態と抗腫瘍免疫との関連を包括的に明らかにする。これらの結果をもとに、MM幹細胞を標的とした新規治療法、および免疫状態を指標とした至適治療法の開発を目指す。

Outline of Final Research Achievements

The purpose of this study was to analyze the expression of immune checkpoint molecules in MM (stem) cells and to characterize the cells responsible for anti-myeloma immunity, and to elucidate the anti-tumor immune mechanism in MM. We found that the expression of immunosuppressive molecules was significantly higher in the stem cell fraction and stronger in relapsed refractory cases than in newly diagnosed cases. A histologic comparison of immune cells in the stem cell population revealed that suppressive cells were induced more in the stem cell population of resistant cases. In addition, immune checkpoint molecules expressed in the stem cell fraction suppressed cytotoxic activity in co-cultures of tumor cells and immune cells, but not specific molecules, indicating that molecules involved in immune suppression differ from case to case. These results provide a useful foundation for future therapeutic strategies targeting anti-myeloma immunity.

Academic Significance and Societal Importance of the Research Achievements

近年、種々がんに対して免疫チェックポイント分子を標的とした治療法が実用化されているが、骨髄腫では、抗PD-1抗体単剤ではほとんど効果が認められていない。この一因として各免疫チェックポイント分子の発現、および機能が症例ごと、さらには病期により異なっていることが明らかとなり、この成果は今後抗骨髄腫免疫を標的とした治療戦略を構築する上で有用な基盤となる。

Research Products

• [Journal Article] CD34+ myeloma cells with self-renewal activities are therapy-resistant and persist as MRD in cell cycle quiescence. (2022)
  • Author(s): Serizawa K; Tanaka H; Ueda T; Fukui A; Kakutani H; Taniguchi T; Inoue H; Kumode T; Taniguchi Y; Rai S; Hirase C; Morita Y; Espinoza JL; Tatsumi Y; Ashida T; Matsumura I
  • Journal Title: Int J Hematol. Volume: 115 Issue: 3 Pages: 336-349
  • DOI: 10.1007/s12185-021-03261-0
  • Peer Reviewed
• [Journal Article] C-type lectin-like receptor 2 specifies a functionally distinct subpopulation within phenotypically defined hematopoietic stem cell population that contribute to emergent megakaryopoiesis (2022)
  • Author(s): Kumode Takahiro、Tanaka Hirokazu、Esipinoza Jorge Luis、Rai Shinya、Taniguchi Yasuhiro、Fujiwara Ryosuke、Sano Keigo、Serizawa Kentaro、Iwata Yoshio、Morita Yasuyoshi、Matsumura Itaru
  • Journal Title: International Journal of Hematology Volume: 115 Issue: 3 Pages: 310-321
  • DOI: 10.1007/s12185-021-03220-9
  • Peer Reviewed
• [Journal Article] Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide (2022)
  • Author(s): Shimazu Y, Kanda J, Kaneko H, Imada K, Yamamura R, Kosugi S, Shimura Y, Ito T, Fuchida SI, Uchiyama H, Fukushima K, Yoshihara S, Hanamoto H, Tanaka H, Uoshima N, Ohta K, Yagi H, Shibayama H, Onda Y, Tanaka Y, Adachi Y, Matsuda M, Iida M, Miyoshi T, Matsui T, Takahashi R, et al. Kansai Myeloma Forum.
  • Journal Title: Therapeutic Advances in Hematology Volume: 13
  • DOI: 10.1177/20406207221142487
  • Peer Reviewed
• [Journal Article] Real-world effectiveness and safety analysis of carfilzomib-lenalidomide-dexamethasone and carfilzomib-dexamethasone in relapsed/refractory multiple myeloma: a multicenter retrospective analysis (2022)
  • Author(s): Onda Y, Kanda J, Kaneko H, Shimura Y, Fuchida SI, Nakaya A, Itou T, Yamamura R, Tanaka H, Shibayama H, Shimazu Y, Uchiyama H, Yoshihara S, Adachi Y, Matsuda M, Hanamoto H, Uoshima N, Kosugi S, Ohta K, Yagi H, Kanakura Y, Matsumura I, Hino M, Nomura S, Shimazaki C, Takaori-Kondo A, Kuroda J; Kansai Myeloma Forum.
  • Journal Title: Therapeutic Advances in Hematology Volume: 13
  • DOI: 10.1177/20406207221104584
  • Peer Reviewed
• [Journal Article] Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells (2022)
  • Author(s): Fujiwara Ryosuke、Taniguchi Yasuhiro、Rai Shinya、Iwata Yoshio、Fujii Aki、Fujimoto Ko、Kumode Takahiro、Serizawa Kentaro、Morita Yasuyoshi、Espinoza J. Luis、Tanaka Hirokazu、Hanamoto Hitoshi、Matsumura Itaru
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 626 Pages: 156-166
  • DOI: 10.1016/j.bbrc.2022.08.010
  • Peer Reviewed
• [Journal Article] Decreased expression of T‐cell‐associated immune markers predicts poor prognosis in patients with follicular lymphoma (2021)
  • Author(s): Rai Shinya、Inoue Hiroaki、Sakai Kazuko、Hanamoto Hitoshi、Matsuda Mitsuhiro、Maeda Yasuhiro、Haeno Takahiro、Watatani Yosaku、Kumode Takahiro、Serizawa Kentaro、Taniguchi Yasuhiro、Hirase Chikara、Espinoza J. Luis、Morita Yasuyoshi、Tanaka Hirokazu、Ashida Takashi、Tatsumi Yoichi、Nishio Kazuto、Matsumura Itaru
  • Journal Title: Cancer Science Volume: 113 Issue: 2 Pages: 660-673
  • DOI: 10.1111/cas.15224
  • Peer Reviewed / Open Access
• [Journal Article] Potent efficacy of chlorpromazine in acute myeloid leukemia harboring KIT-D816V mutation (2021)
  • Author(s): Rai Shinya、Tanaka Hirokazu、Espinoza J. Luis、Kumode Takahiro、Matsumura Itaru
  • Journal Title: Leukemia Research Reports Volume: 15 Pages: 100256-100256
  • DOI: 10.1016/j.lrr.2021.100256
  • Peer Reviewed / Open Access
• [Journal Article] Low absolute lymphocyte count is a poor prognostic factor for untreated advanced follicular lymphoma treated with rituximab plus bendamustine: results of the prospective phase 2 CONVERT trial (2021)
  • Author(s): Rai Shinya、Inoue Hiroaki、Hanamoto Hitoshi、Matsuda Mitsuhiro、Maeda Yasuhiro、Wada Yusuke、Haeno Takahiro、Watatani Yosaku、Kumode Takahiro、Hirase Chikara、Espinoza J. Luis、Morita Yasuyoshi、Tanaka Hirokazu、Tatsumi Yoichi、Matsumura Itaru
  • Journal Title: International Journal of Hematology Volume: 114 Issue: 2 Pages: 205-216
  • DOI: 10.1007/s12185-021-03148-0
  • Peer Reviewed / Open Access
• [Journal Article] Plateau is a prognostic factor of lenalidomide therapy for previously treated multiple myeloma (2021)
  • Author(s): Takakuwa Teruhito、Ohta Kensuke、Nakatani Eiji、Ito Tomoki、Kaneko Hitomi、Fuchida Shin‐Ichi、Shimura Yuji、Yagi Hideo、Shibayama Hirohiko、Kanda Junya、Uchiyama Hitoji、Kosugi Satoru、Tanaka Hirokazu、Kawata Eri、Uoshima Nobuhiko、Ishikawa Jun、Shibano Masaru、Karasuno Takahiro、Shindo Maki、Shimizu Yoshifumi、等
  • Journal Title: Hematological Oncology Volume: 未定 Issue: 3 Pages: 349-357
  • DOI: 10.1002/hon.2863
  • Peer Reviewed / Open Access
• [Journal Article] Outcomes of ixazomib/lenalidomide/dexamethasone for multiple myeloma: A multicenter retrospective analysis. (2021)
  • Author(s): Takakuwa T, Yamamura R, Ohta K, Kaneko H, Imada K, Nakaya A, Fuchida SI, Shibayama H, Matsuda M, Shimazu Y, Adachi Y, Kosugi S, Uchiyama H, Tanaka H, Hanamoto H, Shimura Y, Kanda J, Onda Y, Uoshima N, Yagi H, Yoshihara S, Hino M, Shimazaki C, Takaori-Kondo A, Kuroda J, Matsumura I, Kanakura Y, Nomura S.
  • Journal Title: Eur J Haematol Volume: 106 Issue: 4 Pages: 555-562
  • DOI: 10.1111/ejh.13586
  • Peer Reviewed / Open Access
• [Journal Article] The Impact of Hemodialysis and Liver Cirrhosis on the Plasma Concentrations of Tyrosine Kinase Inhibitors in a Patient with Chronic Myeloid Leukemia (2020)
  • Author(s): Taniguchi Y, Takahashi N, Miura M, Hirase C, Sueda S, Espinoza JL, Rai S, Nakayama S, Serizawa K, Kumode T, Watatani Y, Morita Y, Tanaka H, Matsumura I.
  • Journal Title: Internal Medicine Volume: 59 Issue: 21 Pages: 2745-2749
  • DOI: 10.2169/internalmedicine.4871-20
  • NAID: 130007934222
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-11-01
  • Peer Reviewed / Open Access
• [Journal Article] Pathology and treatment of multiple myeloma understood from the tumor cell-of-origin perspective (2020)
  • Author(s): 田中 宏和
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 9 Pages: 1317-1324
  • DOI: 10.11406/rinketsu.61.1317
  • NAID: 130007937059
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective multi-center study of Adolescent and Young Adult (AYA) Multiple Myeloma in Kansai Myeloma Forum registry. (2020)
  • Author(s): Nakaya A, Kohara T, Shibayama H, Onda Y, Kanda J, Kaneko H, Kosugi S, Ishikawa J, Tanaka H, Fuchida SI, Shimura Y, Ohta K, Shimazaki C, Hino M, Takaori-Kondo A, Kuroda J, Matsumura I, Kanakura Y, Nomura S; Kansai Myeloma Forum Investigators.
  • Journal Title: Int J Hematol Volume: 112 Issue: 4 Pages: 435-438
  • DOI: 10.1007/s12185-020-02996-6
  • Peer Reviewed / Open Access
• [Journal Article] Targeted therapy for medullary and extramedullary relapse of FLT3-ITD acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation (2020)
  • Author(s): Kumode Takahiro、Rai Shinya、Tanaka Hirokazu、Espinoza J. Luis、Kakutani Hiroaki、Watatani Yosaku、Minamoto Shuji、Taniguchi Yasuhiro、Nakayama Shoko、Morita Yasuyoshi、Ashida Takashi、Matsumura Itaru
  • Journal Title: Leukemia Research Reports Volume: 14 Pages: 100219-100219
  • DOI: 10.1016/j.lrr.2020.100219
  • Peer Reviewed / Open Access
• [Journal Article] Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V. (2020)
  • Author(s): Shinya Rai, Hirokazu Tanaka*, Mai Suzuki, J. Luis Espinoza, Takahiro Kumode, Akira Tanimura, Yasuyoshi Morita, Yoichi Tatsumi, Takafumi Yokota, Kenji Oritani, Toshio Watanabe, Yuzuru Kanakura, and Itaru Matsumura.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 4147-4147
  • DOI: 10.1038/s41467-020-17666-8
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective analysis of plasmacytoma in Kansai Myeloma Forum Registry. (2020)
  • Author(s): Nakaya A, Tanaka H, Yagi H, Ohta K, Shibayama H, Kohara T, Kanda J, Shindo M, Shimura Y, Kosugi S, Kaneko H, Fuchida SI, Uoshima N, Shimazaki C, Hino M, Kuroda J, Kanakura Y, Takaori-Kondo A, Nomura S, Matsumura I; Kansai Myeloma Forum Investigators.
  • Journal Title: Int J Hematol Volume: 112 Issue: 5 Pages: 666-673
  • DOI: 10.1007/s12185-020-02961-3
  • Peer Reviewed / Open Access
• [Journal Article] Tumour‐immune microenvironment in duodenal‐type follicular lymphoma (2020)
  • Author(s): Inoue Hiroaki、Rai Shinya、Tanaka Hirokazu、Espinoza J. Luis、Watatani Yosaku、Kumode Takahiro、Serizawa Kentaro、Nakayama Shoko、Taniguchi Yasuhiro、Morita Yasuyoshi、Tatsumi Yoichi、Ashida Takashi、Matsumura Itaru
  • Journal Title: British Journal of Haematology Volume: 191 Issue: 2 Pages: 243-252
  • DOI: 10.1111/bjh.16715
  • Peer Reviewed / Open Access
• [Journal Article] Introduction by the Guest Editor: Recent advances in biology and treatment of multiple myeloma (2020)
  • Author(s): Tanaka Hirokazu
  • Journal Title: International Journal of Hematology Volume: 111 Issue: 4 Pages: 494-495
  • DOI: 10.1007/s12185-020-02830-z
  • Peer Reviewed / Open Access
• [Journal Article] Epstein?Barr Virus-Induced Post-Transplant Lymphoproliferative Disorder of the Central Nervous System Successfully Treated with Chemo-Immunotherapy (2020)
  • Author(s): Inoue Hiroaki、Rai Shinya、Tanaka Hirokazu、Espinoza J. Luis、Komori-Inoue Maiko、Kakutani Hiroaki、Minamoto Shuji、Kumode Takahiro、Nakayama Shoko、Taniguchi Yasuhiro、Morita Yasuyoshi、Okuda Takeshi、Tatsumi Yoichi、Ashida Takashi、Matsumura Itaru
  • Journal Title: Viruses Volume: 12 Issue: 4 Pages: 416-416
  • DOI: 10.3390/v12040416
  • Peer Reviewed / Open Access
• [Presentation] Impact of cytogenetic abnormalities in MM of real world data; Retrospective analysis of KMF (2022)
  • Author(s): 柴山 浩彦、志村 勇司、伊藤 量基、魚嶋 伸彦、山村 亮介 、淵田 真一、金子 仁臣、今田 和典 小杉 智、松井 利充、吉原 哲 、内山 人二、松田 光弘、恩田 佳幸、田中 康博、花本 仁、高桑 輝人、田中 宏和、福島 健太郎、太田 健介、諫田 淳也、八木 秀男、日野 雅之、保仙 直毅、野村 昌作、島崎 千尋、高折 晃史、松村 到、黒田 純也
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Updated real-world data of 2572 patients with symptomatic myeloma registered in Kansai Myeloma Forum (2022)
  • Author(s): 柴山 浩彦、伊藤 量基、金子 仁臣、今田 和典、山村 亮介、小杉 智、淵田 真一、諫田 淳也、田中 宏和、花本 仁、魚嶋 伸彦、福島 健太郎、吉原 哲、太田 健介、田中 康博、高橋 良一、松井 利充、松田 光弘、河田 英里、恩田 佳幸、高桑 輝人、八木 秀男、野村 昌作、島崎 千尋、高折 晃史、松村 到、保仙 直毅、日野 雅之、黒田 純也
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Predicting the durable efficacy of elotuzumab by lymphocyte counts and free light chain ratio (2022)
  • Author(s): 諌田 淳也、小杉 智、伊藤 量基、今田 和典、志村 勇司、淵田 真一、福島 健太郎、田中 宏和、吉原 哲、太田 健介、魚嶋 伸彦、八木 秀男、柴山 浩彦、山村 亮介、田中 康博、内山 人二、恩田 佳幸、足立 陽子、花本 仁、高橋 良一、松田 光弘、高桑 輝人、日野 雅之、保仙 直毅、野村 昌作、島崎 千尋、松村 到、高折 晃史、黒田 純也
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] 同種造血幹細胞移植におけるレテルモビルの有用性の検討 (2021)
  • Author(s): 谷口康博、平瀬主税、芦田隆司、波江野高大、角谷 宏明、源 周治、綿谷 陽作、 口分田貴裕、芹澤憲太郎、頼 晋也、森田 泰慶、田中 宏和、辰巳 陽一、松村 到
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] 腫瘍起源からみた多発性骨髄腫の病態と治療 (2020)
  • Author(s): 田中宏和
  • Organizer: 第82回日本血液学会学術集会