Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology Pub Date : 2024-03-25 DOI:10.1002/cti2.1500

Jingjing Pu, Amit Sharma, Ting Liu, Jian Hou, Ingo GH Schmidt-Wolf

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Abstract

Objectives

The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine-induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study.

Methods

We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilising various in vitro methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions.

Results

The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN-γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings.

Conclusions

Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.

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组蛋白去乙酰化酶抑制剂的协同整合显然能通过NKG2D途径提高细胞因子诱导的多发性骨髓瘤杀伤细胞的效率

目的人们迅速认识到表观遗传操作在限制癌细胞能力方面的潜力，这推动了包括组蛋白去乙酰化酶抑制剂（HDACis）在内的转化项目的开展。对多发性骨髓瘤（MM）的临床试验表明，HDACis 具有显著疗效，细胞因子诱导的杀伤细胞（CIK）免疫疗法也取得了令人鼓舞的成果。耐人寻味的是，HDACis 和 CIK 细胞免疫疗法在 MM 中的协同作用尚未被探索，这促使我们开展了这项研究。方法我们研究了与临床相关的 HDACis（panobinostat/LBH589 和 romidepsin）以及来自不同 MM 细胞系（U266、RPMI8226、OPM-2 和 NCI-H929）外周血单核细胞的 CIK 细胞。利用各种体外方法，我们研究了 HDACis 如何通过 NKG2D/NKG2D 配体的相互作用增强 CIK 细胞对骨髓瘤细胞的溶解。结果我们的分析结果表明了几个重要发现。(1）与 HDACis 结合使用时，CIK 细胞对 MM 细胞的细胞毒性增强。(2）细胞凋亡显著增加，表明 HDACis 和 CIK 可共同增强特定 MM 细胞系的细胞凋亡效应。(3）由于 HDACis 的独立活性，IFN-γ 分泌增加，颗粒酶 B 分泌发生变化。(4）值得注意的是，HDACis 增加了对诱导 NKT 细胞抗肿瘤细胞毒性至关重要的 MICA/B 和 ULBP2 的表达。用纯化的小鼠抗人 NKG2D 抗体阻断 CIK 细胞中的 NKG2D 受体进一步证实了我们的发现。结论我们的分析提供了足够的证据，可将这一临床上被遗忘的实例（HDACis-CIK 细胞组合）视为 MM 治疗的优先选择。此外，我们还发现，激活 NK/NKT 细胞的 NKG2D/NKG2D 配体相互作用可能有助于增强 CIK 细胞对 HDACis 治疗的骨髓瘤细胞裂解反应。

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来源期刊

Clinical & Translational Immunology Medicine-Immunology and Allergy

CiteScore

12.00

自引率

1.70%

发文量

审稿时长

13 weeks

期刊介绍： Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.