CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway.
Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway.
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我们的分析提供了充分的证据，认为这一临床上被遗忘的实例（HDACis-CIK 细胞联合）可作为 MM 治疗的治疗优先事项。此外，我们认为 NKG2D/NKG2D-配体相互作用激活 NK/NKT 细胞可能有助于增强 CIK 细胞对 HDACis 治疗应答中的骨髓瘤细胞裂解。
表观遗传调控在限制癌细胞能力方面的潜力被迅速认识，推动了包括组蛋白去乙酰化酶抑制剂（HDACis）在内的转化研究。多发性骨髓瘤（MM）的临床试验显示HDACis具有显著获益，同时细胞因子诱导的杀伤细胞（CIK）免疫治疗也展现出良好前景。有趣的是，HDACis与CIK细胞免疫治疗在MM中的协同作用尚未被探索，这促使我们开展了本研究。
我们检测了临床相关的HDACis（panobinostat/LBH589和romidepsin）以及源自外周血单核细胞的CIK细胞，在多种MM细胞系（U266、RPMI8226、OPM-2和NCI-H929）中的作用。利用多种体外方法，我们研究了HDACis如何通过NKG2D/NKG2D配体相互作用增强CIK细胞对骨髓瘤细胞的裂解。
我们的分析结果显示了几个关键发现。(1) HDACis与CIK细胞联合使用时，对MM细胞的细胞毒性增强。(2) 细胞凋亡显著增加，提示HDACis和CIK可能在特定MM细胞系中共同增强凋亡效应。(3) 由于HDACis的独立活性，IFN-γ分泌升高，颗粒酶B分泌发生改变。(4) 值得注意的是，HDACis增加了MICA/B和ULBP2的表达，这对于诱导NKT细胞的抗肿瘤细胞毒性至关重要。使用纯化的小鼠抗人NKG2D抗体在CIK细胞中进行NKG2D受体阻断验证，进一步支持了我们的发现。
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.
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.
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.
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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