Host innate immune mechanisms separating inflammatory or lymphoproliferative diseases in HTLV-1 infection

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07512
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Kansai Medical University (2022); Tokyo Medical and Dental University (2020-2021)
• Principal Investigator: KANNAGI Mari 関西医科大学, 医学部, 教授 (80202034)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: HTLV-1 / 自然免疫 / 腫瘍 / 炎症 / ATL / EZH2 / Lenalidomide / STAT3

Outline of Final Research Achievements

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in separate groups of HTLV-1-infected individuals. In our previous study, we suggested that the IL-10-STAT3 pathway could be a candidate of host factors that separate malignant tumor and inflammation. In this study, we aimed to find factors regulating IL-10-STAT3 pathway in HTLV-1-infected cells. Among the reagents used as a probe, Lenalidomide suppressed IL-10-STAT3 pathway in HTLV-1-infected cells. Unexpectedly, Lenalidomide also suppressed EZH2, an epigenetic regulator known to promote oncogenesis. Lenalidomide is an immunomoduratory drug that has been used to treat multiple myeloma and recently been approved for relapsed /recurrent ATL. Our results not only indicate the importance of IL-10-STAT3 pathway in tumor development in HTLV-1 infection, but also discovered a new link between Lenalidomide and epigenetic regulation.

Free Research Field

腫瘍免疫・感染免疫

Academic Significance and Societal Importance of the Research Achievements

Lenalidomideは再発・難治ATLの治療薬としてすでに承認されているがその機序には不明点が多い。ATLに一定の効果を示すLenalidomideがSTAT3経路を抑制したことは、STAT3経路がHTLV-1感染からATLへの進展に重要であることを裏付けている。さらに、このSTAT3経路の調節にEZH2が関与している可能性が示唆された。また、Lenalidomideは多発性骨髄腫にも汎用される薬剤であるが、EZH2を負に制御しエピジェネティックな作用を持つことは今回初めて明らかになった知見であり、Lenalidomideのような免疫調節薬の多彩な作用を説明する新たな機序と考えられる。