Development of new treatment for DLBCL through the analysis of microenvironment in combination with genomic alteration
| Project/Area Number |
19K08818
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kyushu University |
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Principal Investigator |
Koji Kato 九州大学, 大学病院, 講師 (20571764)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 悪性リンパ腫 / ゲノム変異 / 微小環境 / 遺伝子変異 / リンパ腫周囲環境 / びまん性大細胞型B細胞リンパ腫 |
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| Outline of Research at the Start |
本研究では、DLBCLのリンパ腫細胞の遺伝子変化が、どのような免疫機構（サイトカインやB-T細胞相互作用など）を介して、DLBCLの悪性度と相関する特徴的な微小環境を形成するのか、そのメカニズムを明らかにする。さらに、リンパ腫細胞とその周囲微小環境から構成されるDLBCL病変を包括的に評価した新たな層別化スコアの作成を試み、治療標的となるようなシグナル伝達経路や分子を同定、リンパ腫細胞とその周囲微小環境の双方を標的としうる新規治療法の開発を目指す。
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| Outline of Final Research Achievements |
Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis. Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells in lymphoma tissue indicates a positive therapeutic response. Our prognostic model clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells. These data suggest that the loss of GC-microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of unfavorable molecular signatures.
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| Academic Significance and Societal Importance of the Research Achievements |
現状、DLBCLのリンパ腫細胞のみを標的とする治療開発には、一定の限界があると言わざるを得ない。一方、キメラ抗原受容体T細胞（CAR-T）療法や免疫チェックポイント阻害薬などに代表される免疫治療は、この限界を克服する可能性がある治療として期待されている。今後、これら免疫治療の開発において、その効果を左右する微小環境の理解は必須であり、本研究はその入口となりうる成果と考えられる。
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Report
(4 results)
Research Products
(29 results)
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[Journal Article] A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.2022
Author(s)
Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.
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Journal Title
Blood Adv.
Volume: 6
Issue: 7
Pages: 2388-2402
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma.2022
Author(s)
Kato K, Makita S, Goto H, Kanda J, Fujii N, Shimada K, Akashi K, Izutsu K, Teshima T, Fukuda N, Sumitani T, Sumi H, Shimizu S, Kakurai Y, Yoshikawa K, Tobinai K, Usui N, Hatake K.
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Journal Title
Int J Clin Oncol.
Volume: 27
Issue: 1
Pages: 213-223
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Phase 2 Study of Tazemetostat for Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma with EZH2 Mutation in Japan.2021
Author(s)
Izutsu K, Ando K, Nishikori M, Shibayama H, Teshima T, Kuroda J, Kato K, Imaizumi Y, Nosaka K, Sakai R, Hojo S, Nakanishi T, Rai S.
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Journal Title
Cancer Sci.
Volume: 62
Issue: 7
Pages: 3627-3635
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 study2020
Author(s)
Miyazaki K, Asano N, Yamada T, Miyawaki K, Sakai R, Igarashi T, Nishikori M, Ohata K, Sunami K, Yoshida I, Yamamoto G, Takahashi N, Okamoto M, Yano H, Nishimura Y, Tamaru S, Nishikawa M, Izutsu K, Kinoshita T, Suzumiya J, Ohshima K, Kato K, Katayama N, Yamaguchi M
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Journal Title
Haematologica
Volume: -
Issue: 9
Pages: 2308-2315
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A retrospective analysis of haplo-identical HLA-mismatch hematopoietic transplantation without posttransplantation cyclophosphamide for GVHD prophylaxis in patients with adult T-cell leukemia-lymphoma.2019
Author(s)
Yoshimitsu M, Utsunomiya A, Fuji S, Fujiwara H, Fukuda T, Ogawa H, Takatsuka Y, Ishitsuka K, Yokota A, Okumura H, Ishii K, Nishikawa A, Eto T, Yonezawa A, Miyashita K, Tsukada J, Tanaka J, Atsuta Y, Kato K.
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Journal Title
Bone Marrow Transplant.
Volume: 印刷中
Issue: 8
Pages: 1266-1274
DOI
Related Report
Peer Reviewed / Open Access
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