CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma.
Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma.
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我们的研究结果表明，利用 huB10G5 靶向可溶性 MIC 可能是促进 MM 中 NKG2D 依赖性细胞免疫治疗疗效的一种可行治疗策略。
主要组织相容性复合体（MHC）I类链相关蛋白（MIC）是一种在进展过程中由多发性骨髓瘤（MM）细胞释放的应激诱导配体，可溶性MIC会损害NK 细胞2族D（NKG2D）活化受体介导的自然杀伤（NK）细胞识别和功能。然而，用单克隆抗体（mAb）清除可溶性MIC能否恢复MM患者的NK细胞活性仍尚未确定。
我们分析了癌症基因组图谱（TCGA）多发性骨髓瘤研究基金会（MMRF）CoMMpass数据集，以检验MIC表达在MM中的预后意义。我们通过ELISA检测了初诊MM患者配对外周血（PB）和骨髓（BM）血浆中可溶性MIC的水平。我们通过多色流式细胞术评估了可溶性MIC水平与MM患者NK细胞免疫表型之间的相关性。我们还构建了过表达MIC的MM细胞系，并表征了在可溶性MIC存在下患者NK细胞的细胞毒性功能，同时检验了用人源化mAb（huB10G5）清除可溶性MIC的影响。
我们通过揭示来自 TCGA MMRF CoMMpass 数据集中 MICA 高表达患者的总体生存率显著更优，刻画了 MICA 在 MM 中的重要性。可溶性 MICA 的水平在 MM 中比在前驱阶段升高得更明显，并且可溶性 MICA 的浓度在 BM 血浆中高于 PB。BM 中可溶性 MICA 的浓度与骨髓瘤负荷相关，而在 MM 患者诊断性 BM 抽吸物中，它与 NKG2D + NK 细胞的频率呈负相关。可溶性 MICA 下调了 NKG2D 表达，并降低了 MM 患者 NK 细胞的离体细胞毒性，而一种人源化可溶性 MIC 清除 mAb（huB10G5）可逆转这些变化，并增强 NK 细胞的脱颗粒。
Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition and function of natural killer (NK) cells. However, whether clearing soluble MIC with a monoclonal antibody (mAb) can restore NK cell activity of MM patients remains undetermined.
We analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance of MIC expression in MM. We examined the level of soluble MIC in paired peripheral blood (PB) and bone marrow (BM) plasma of patients with MM at diagnosis by ELISA. We evaluated the correlation between the level of soluble MIC and immunophenotype of NK cells from MM patients by multicolor flow cytometry. We also generated MIC-overexpressing MM cell line and characterized the cytotoxic function of patient NK cells in the presence of soluble MIC, and examined the impact of clearing soluble MIC with a humanized mAb (huB10G5).
We characterize the importance of MICA in MM by revealing the significantly better overall survival of patients with high MICA expression from TCGA MMRF CoMMpass data set. The level of soluble MICA is more highly elevated in MM than in precursor stages, and the concentration of soluble MICA is higher in BM plasma than in PB. The concentration of soluble MICA in BM was correlated with myeloma burden, while it was negatively correlated with the frequency of NKG2D + NK cells in diagnostic BM aspirates of MM patients. Soluble MICA downregulated NKG2D expression and decreased cytotoxicity of MM patient NK cells ex vivo , which were reversed by a humanized soluble MIC-clearing mAb (huB10G5) with enhanced degranulation of NK cells.
Our findings indicate targeting soluble MIC with huB10G5 might be a viable therapeutic approach to promote NKG2D-dependent cellular immunotherapy outcome in MM.
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