2022 Fiscal Year Final Research Report
Clarifying the function of inflammatory cells with epigenomic abnormalities in angioimmunoblastic T-cell lymphoma
| Project/Area Number |
21K16239
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Keywords | がん微小環境 / クローン性造血 / T細胞リンパ腫 |
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| Outline of Final Research Achievements |
Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas G17V RHOA mutation in immature cells with TET2 mutations promotes the development of T follicular helper-like tumor cells. Here, we investigated the mechanism by which TET2-mutant immune cells enable AITL development. Among 2 mouse models, mice lacking Tet2 in all blood cells spontaneously developed AITL, while mice lacking Tet2 only in T cells did not. Therefore, Tet2-deficient immune cells function as a niche for AITL development. In silico analysis using scRNA-seq data identified Cd40-Cd40lg as a possible mediator of aberrant expanded GCB and tumor cell interactions. Treatment of AITL mice with anti-Cd40lg inhibitory antibody prolonged survival. Therefore, ACH-derived GCB cells could undergo independent clonal evolution and support the tumorigenesis in AITL via the CD40-CD40LG axis.
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| Free Research Field |
血液内科学
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| Academic Significance and Societal Importance of the Research Achievements |
クローン性造血を背景にもつ血管免疫芽球性T細胞リンパ腫のマウスモデルを用いて単一細胞レベルでの遺伝子発現解析を行なった。インシリコ解析から、胚中心B細胞と「がん細胞」の相互作用分子として、CD40-CD40LG経路が明らかとなった。また、CD40-CD40LG経路を阻害する治療によって、「がん」そのものの増殖を抑えることができることを発見した。本研究結果は、がん微小環境細胞と「がん細胞」のネットワークを阻害するという新しい治療法を提案するものであり、このような治療アプローチは、血管免疫芽球性T細胞リンパ腫のような希少がんのアンメットメディカルニーズに答えるものと考えられる。
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