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

2020 Fiscal Year Final Research Report

• 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
• Keywords: 悪性リンパ腫 / 免疫微小環境 / 免疫逃避機構

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.

Free Research Field

血液内科学

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。