Expansion of Th1-like gamma delta T cells by new generation IMiDs and their cytotoxicity against myeloma progenitors

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokushima
• Principal Investigator: MIKI Hirokazu 徳島大学, 病院, 講師 (50511333)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: γδＴ細胞 / 多発性骨髄腫 / 免疫調節薬

Outline of Final Research Achievements

After PBMCs isolated from normal donors were incubated for one week with Zol and IMiDs (LEN or POM) in combination, γδT cells were robustly expanded. The expanded γδT cells expressed intracellular IFN-γ but not Foxp3 along with increased surface expression of NKG2D and DNAM-1, indicating induction of Th1-like γδT cells. Interestingly, the expanded γδT cells also markedly minimized the sizes of side populations in RPMI8226 and KMS-11 cells, and suppressed their clonogenic capacity as determined by in vitro colony formation and tumorigenic capacity in SCID mice, suggesting targeting a drug-resistant clonogenic MM cells. SMI-16a,Pim inhibitor, upregulated surface expression of HSP70 on MM cells. Pretreatment with SMI-16a further potentiate the cytotoxic activity of γδT cells against MM cells. Combination with novel anti-MM agents warrants further study in terms of further enhancement of anti-MM effects with the ex-vivo expanded Th1-like γδT cells.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究では、Th1機能を増強させた抗腫瘍活性のより強いγδT細胞を体外で大量に誘導するため合成IPPによるγδTCRの直接刺激と免疫腑活作用を有する抗骨髄腫薬（IMiDs）という新規の併用法を用いる点、誘導したTh1様γδT細胞の抗腫瘍効果を高まるためにADCC活性を惹起する新規抗骨髄腫薬を用いる点、γδT細胞を腫瘍残存部で活性化させ残存腫瘍細胞を駆逐しようとする点に独創性を有している。免疫調節薬を用い癌前駆細胞や癌幹細胞のγδT細胞への感受性を高める試みはこれまでになく、これらの研究により得られる成果は、悪性腫瘍全般に応用可能な新規免疫療法として発展することが期待される。