CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：CREB1 promotes expression of immune checkpoint HLA-E leading to immune escape in multiple myeloma.
CREB1 promotes expression of immune checkpoint HLA-E leading to immune escape in multiple myeloma.
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多发性骨髓瘤细胞可通过免疫逃逸在肿瘤微环境中存活。本研究发现，非经典主要组织相容性复合体I类分子HLA-E是重要的免疫逃逸因素，其表达与t(4;14)、CD56表达等侵袭性疾病特征相关，并可被肿瘤微环境中的干扰素γ诱导。研究显示，转录因子CREB1可直接结合启动子调控HLA-E；基因或药理学抑制CREB1可降低HLA-E，即使存在干扰素或免疫调节药物、帕比司他等诱导因素时也是如此。HLA-E通过结合NKG2A向NK 细胞传递抑制信号。CREB1抑制剂恢复了NK 细胞对多发性骨髓瘤细胞系及患者样本的杀伤作用。结果表明，抑制CREB1可通过限制HLA-E表达、增强NK 细胞活性来促进抗肿瘤免疫。
Multiple myeloma (MM) cells effectively escape anti-tumoral immunity to survive in the tumor microenvironment (TME).
Herein, we identify non-classical major histocompatibility complex (MHC) class I molecule HLA-E as a major contributing factor in immune escape. Clinically, HLA-E expression correlates with aggressive disease features such as t(4;14) and CD56 expression and is induced by IFN-gamma (IFN- ) in the TME.
We discovered that HLA-E is regulated by cAMP responsive element binding protein 1 (CREB1) transcription factor by direct promoter binding; genomic and pharmacological inhibition of CREB1 reduced HLA-E levels even in the presence of IFN- or IFN- activating agents, such as immunomodulatory drugs and panobinostat. HLA-E binds to natural killer group 2A (NKG2A), delivering an inhibitor signal to natural killer (NK) cells. Treatment with a CREB1 inhibitor was able to restore NK cell-mediated cytotoxicity against MM cell lines and patient samples.
In conclusion, our results strongly demonstrate that CREB1 inhibition promotes anti-tumoral immunity in MM by limiting HLA-E expression and enhancing the activity of NK cells.
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