CMTM6 stabilizes PD-L1 expression and regulates its metastasis in Ewing's sarcoma

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K15298
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Yoshimatsu Yuki 国立研究開発法人国立がん研究センター, 研究所, 特任研究員 (60808632)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: ユーイング肉腫 / CMTM6 / 免疫チェックポイント / PD-L1 / miRNA

Outline of Final Research Achievements

Patient-derived cancer model is a pivotal tool to promote cancer research. Ewing’s sarcoma (EWS) is a highly aggressive and metastatic malignant tumor of bone and soft tissues, whose incidence is peak in children and young adulthood. Control of metastasis based on the molecular targeting contributes to improve patient prognosis. To this end, we screened expression of microRNAs in clinical samples to identify target molecules, which regulate malignant properties of EWS cells. Microarray analysis indicated that PD-L1 is significantly down-regulated in the cases with poor prognosis. Although PD-L1 did not affect cell proliferation, it strongly repressed migration of EWS cells. Gene expression analysis revealed that PD-L1 targeted CMTM6, a chemokine-like membrane protein with unknown function. Depletion of CMTM6 by siRNAs strongly inhibited migration of EWS cells. Our data suggest that at least the expression of PD-L1 and CMTM6 is involved in metastasis onset.

Free Research Field

希少がん、肉腫

Academic Significance and Societal Importance of the Research Achievements

CMTM6は免疫チェックポイント分子PD-L1の安定化に必要であることが複数報告されている。エクソソームを介したPD-L1の血中分泌量と免疫チェックポイント阻害剤の奏効性の関連や、PD-L1自身ががん細胞の転移と関連するとの報告がある。腫瘍微小環境中の栄養飢餓状態により腫瘍細胞内のCMTM6の発現上昇に起因する、CMTM6小胞の分泌量の増加はPD-L1阻害剤の不応性のみならず、他の細胞膜レセプターを標的とした治療薬の奏効性にも影響を与える。当初の予定通り、CMTM6の機能解析は進んでおり、生物学的に極めて興味深いデータも多く取得できた。