肿瘤细胞治疗研究
英文原题：Selinexor potentiates NK cell activation against multiple myeloma.
Selinexor potentiates NK cell activation against multiple myeloma.
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这些数据揭示，selinexor 选择性破坏 MM 中的 2A:HLA-E 免疫检查点轴，并增强 NK 细胞活化以及对 MM 细胞的 ADCC。
将 MM 细胞系 (L363、U266、MM.1S) 和从患者骨髓中分离的原代骨髓瘤细胞暴露于 selinexor (50-2000 nM)，并加入或不加入 IFNγ 或 IL-6 以模拟肿瘤微环境 (TME)。通过流式细胞术定量表面 HLA-E 和总 HLA I 类分子。采用免疫印迹和一系列功能试验检测 selinexor 对 NK 细胞抗 MM 效应功能的影响。
Selinexor 下调了 MM 细胞系和原代骨髓瘤细胞表面的 HLA-E 表达。
MM cell lines (L363, U266, MM.1S) and primary myeloma cells isolated from the bone marrow of patients were exposed to selinexor (50-2000 nM) with or without IFNγ or IL-6 to mimic the tumour microenvironment (TME). Surface HLA-E and total HLA class I were quantified by flow cytometry. Immunoblotting and a range of functional assays were used to examine the effect of selinexor on NK cell effector function against MM.
Selinexor downregulated surface HLA-E expression on MM cell lines and primary myeloma cells. This improved the activation of NKG2A+ NK cells, NK cell-specific lysis of MM cell lines and antibody-dependent cellular cytotoxicity (ADCC) with the therapeutic antibodies daratumumab and elotuzumab. This improvement was also observed in the presence of TME-mimicking signals IFNγ and IL-6. Pre-treatment of MM cells with selinexor for 24 hours prior to daratumumab resulted in optimal ADCC. DISCUSSION: These data reveal that selinexor selectively disrupts the NKG2A:HLA-E immune checkpoint axis in MM and enhances NK cell activation and ADCC against MM cells. These findings provide a mechanistic rationale for investigating combinations of selinexor with approved therapeutic antibodies in MM and suggest that treatment timing may be an important consideration in the design of combination regimens.
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