CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Natural killer cells efficiently target multiple myeloma clonogenic tumor cells.
Natural killer cells efficiently target multiple myeloma clonogenic tumor cells.
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过去几年多发性骨髓瘤（MM）的治疗格局已有变化，但多数患者最终仍会复发，因为现有治疗未能靶向具有耐药和自我更新能力的克隆形成性干细胞。研究者假设侧群（SP）细胞代表骨髓瘤克隆形成性干细胞，并分析 NK 细胞对这些细胞的抗骨髓瘤活性以探索新疗法。从 MM 患者获取 NK 细胞，与 K562-mb15-41BBL 细胞系共培养，制备活化扩增 NK（NKAE）细胞产品，并以流式细胞术表征。通过 Eu-TDA 释放试验和甲基纤维素克隆形成试验评估其对 MM 细胞的功能；以 Dye Cycle Violet 标记检测 SP，并以流式细胞术和 RNA 测序表征；通过克隆形成试验检测自我更新能力，并分选两类细胞进行延时显微成像。SP 细胞具有自我更新潜能，且干细胞代谢相关基因过表达。MM 患者 NK 细胞功能失调，对克隆形成性细胞的抗肿瘤活性低于健康供者 NK 细胞。患者 NK 细胞经活化扩增后恢复细胞毒活性，可特异性杀伤骨髓瘤克隆形成细胞，并表现为高细胞毒表型、表达 NKG2D 受体。阻断 NKG2D 会降低 NK 细胞对克隆形成性骨髓瘤细胞的活性；活化 NK 细胞可杀伤表达 NKG2D 配体的 SP 细胞。SP 细胞可能构成 MM 的干细胞群。本研究首次报告了 NK 细胞对骨髓瘤克隆形成性细胞的活性。
The multiple myeloma (MM) landscape has changed in the last few years, but most patients eventually relapse because current treatment modalities do not target clonogenic stem cells, which are drug-resistant and can self-renew.
We hypothesized that side population (SP) cells represent myeloma clonogenic stem cells and, searching for new treatment strategies, analyzed the anti-myeloma activity of natural killer (NK) cells against clonogenic cells. Activated and expanded NK cells (NKAE) products were obtained by co-culturing NK cells from MM patients with K562-mb15-41BBL cell line and characterized by flow cytometry. Functional experiments against MM cells were performed by Eu-TDA release assays and methylcellulose clonogenic assays. Side population was detected by Dye Cycle Violet labeling and then characterized by flow cytometry and RNA-Seq. Self-renewal capacity was tested by clonogenic assays. Sorting of both kind of cells was performed for time-lapse microscopy experiments.
SP cells exhibited self-renewal potential and overexpressed genes involved in stem cell metabolism. NK cells from MM patients exhibited dysregulation and had lower anti-tumor potential against clonogenic cells than healthy donors' NK cells. Patients' NK cells were activated and expanded. These cells recovered cytotoxic activity and could specifically destroy clonogenic myeloma cells.
They also had a highly cytotoxic phenotype expressing NKG2D receptor. Blocking NKG2D receptor decreased NK cell activity against clonogenic myeloma cells, and activated NK cells were able to destroy SP cells, which expressed NKG2D ligands. SP cells could represent the stem cell compartment in MM. This is the first report describing NK cell activity against myeloma clonogenic cells.
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