Molecular mechanism of immunoreceptor SLAMF3 in myeloma pathogenesis and development of new SLAMF3-targeted therapy

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K16196
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Nippon Medical School
• Principal Investigator: Ishibashi Mariko 日本医科大学, 医学部, 助教 (20599047)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 多発性骨髄腫 / SLAMF3 / CD229 / ERKシグナル / 腫瘍悪性化 / 免疫治療 / 腫瘍微小環境

Outline of Final Research Achievements

To determine whether the new immunoreceptor SLAMF3 is useful as a new therapeutic target in advanced or refractory/relapsed multiple myeloma, this study aimed to define the expression and biologic functions of SLAMF3 in myeloma. SLAMF3 was highly and constitutively expressed on plasma cells from myeloma patients regardless of disease stage. SLAMF3 molecules on myeloma cells transmitted MAPK/ERK signals mediated via the complex of SHP2 and GRB2 by self-ligand interaction between myeloma cells, and upregulated cyclin D1/2 and BCL2 genes, suggesting that SLAMF3 promote a high malignant potential in myeloma. SLAMF3 molecules in myeloma may be not only new cell surface markers but also a new therapeutic target of immunotherapy and novel agents such as small-molecule inhibitors.

Free Research Field

多発性骨髄腫、腫瘍免疫、分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究で着目したSLAMF3分子は、多発性骨髄腫において、病期に関わらず高発現しており、更に、細胞増殖能の亢進や薬剤耐性の獲得を介して骨髄腫の増悪化・病勢進行に深く関わることを示した。これら結果より、SLAMF3は再発難治の骨髄腫患者において、アグレッシブな臨床病態に至る機序に関与している可能性が示唆された。このことから、本研究の結果はSLAMF3を標的とした抗体療法やCAR-T療法の治療開発、治療戦略に重要な知見を与えるという点で今後の骨髄腫治療に重要な意義がある。更に、骨髄腫の免疫治療へ大きな貢献が期待される。