Molecular mechanisms underlying the induction of myeloid-derived suppressor cells in multiple myeloma

• Project/Area Number: 18K16125
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Shimura Yuji 京都府立医科大学, 医学(系)研究科(研究院), 助教 (00714685)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨髄由来抑制細胞 / 多発性骨髄腫 / CCL5 / MIF / 抗腫瘍免疫 / 免疫調整薬 / サイトカイン / 免疫調節薬 / MDSC / 免疫療法 / 骨髄由来免疫抑制細胞 / 腫瘍免疫 / 分子標的剤

Outline of Final Research Achievements

We investigated the mechanisms underlying myeloid-derived suppressor cell (MDSC) induction in multiple myeloma (MM). Using a transwell co-culture system, a part of human myeloma-derived cell lines were potent in inducing MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of C-Cmotif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of downregulation of CCL5 and MIF in myeloma cells; and downregulation of CCR5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. Totally, ,we identified a novel effect of IMiD of inhibiting MDSC induction via overlapping regulatory effects in myeloma cells and normal PBMCs.

Academic Significance and Societal Importance of the Research Achievements

近年、腫瘍に対する免疫療法は、従来の治療に難治性であった患者に対しても劇的な効果を示す可能性があることから注目を浴びている。一方で、免疫療法に対する治療抵抗性の一因に腫瘍による免疫抑制が挙げられており、その克服が課題となっている。本研究は、腫瘍による免疫抑制の主体と考えられている骨髄由来抑制細胞がどのように誘導されるかを一部解明したものであり、今後、骨髄由来抑制細胞を制御し、免疫療法の効果を高める戦略を開発する上での礎となると考えている。また、既存の多発性骨髄腫に対する薬による骨髄由来抑制細胞への効果についても解明しており、今後の治療反応性予測などにも応用できる可能性がある。

Research Products

• [Journal Article] Lenalidomide and pomalidomide potently interfere with induction of myeloid-derived suppressor cells in multiple myeloma (2020)
  • Author(s): Kuwahara-Ota S, Shimura Y, Steinebach C, Isa R, Yamaguchi J, Nishiyama D, Fujibayashi Y, Takimoto-Shimomura T, Mizuno Y, Matsumura-Kimoto Y, Tsukamoto T, Chinen Y, Kobayashi T, Horiike S, Taniwaki M, Gutschow M, Kuroda J
  • Journal Title: Br J Haematol Volume: 191 Issue: 5 Pages: 784-795
  • DOI: 10.1111/bjh.16881
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 多発性骨髄腫における骨髄由来免疫抑制細胞に対するIMiDsの抑制効果 (2019)
  • Author(s): 太田沙絵子、志村勇司 他
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Myeloma-induced myeloid-derived suppressor cells are targeted by immunomodulatory drugs that regulate the CCL5/CCR5 axis and MIF and IRF8 expression (2019)
  • Author(s): 太田沙絵子、志村勇司 他
  • Organizer: The annual congress of EHA (European Hematology Association）
  • Int'l Joint Research
• [Presentation] Potency of immunomodulatory drugs in interfering molecular mechanisms underlying the induction of myeloid-derived suppressor cell in multiple myeloma (2019)
  • Author(s): 太田沙絵子
  • Organizer: 第44回日本骨髄腫学会学術集会