RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
NK 细胞治疗可能增强贝伐珠单抗联合伊立替康在胶质母细胞瘤小鼠模型中的抗肿瘤效果
英文原题：Natural killer cell therapy potentially enhances the antitumor effects of bevacizumab plus irinotecan in a glioblastoma mouse model.
查看英文原题
Natural killer cell therapy potentially enhances the antitumor effects of bevacizumab plus irinotecan in a glioblastoma mouse model.
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中文摘要
针对恶性脑肿瘤细胞异质性，可通过联合具有不同抗肿瘤机制的疗法，达到有效治疗所需的作用阈值。本研究调查自然杀伤（NK）细胞与贝伐珠单抗（Bev）联合伊立替康（Iri）治疗多形性胶质母细胞瘤（GBM）的效果。实验设计中，研究者使用表达OX40配体及膜结合IL-18和IL-21的K562细胞扩增并活化NK细胞。通过MTT实验和流式细胞术评估Bev、Iri对GBM细胞增殖及NK配体表达的影响；通过体外LDH实验评估NK细胞对Bev加Iri处理后GBM细胞的细胞毒作用。研究者在U87异种移植NOD/SCID IL-12R缺失小鼠模型中，结合不同剂量Bev和Iri以及不同数量、不同途径注射的NK细胞，根据皮下和颅内肿瘤大小及生存情况验证治疗效果。
通过离体流式细胞术和免疫组织化学检测注入的NK细胞是否存在于肿瘤中。结果发现，Iri会影响GBM细胞增殖和NK配体表达，而Bev未导致这些细胞过程出现差异；不过，在U87颅内模型中，Bev会调节Iri疗效。NK细胞显著增强对Bev和Iri处理后GBM细胞的体外细胞毒作用。在U87皮下模型中，静脉注射NK细胞联合Bev和Iri显著降低肿瘤体积；但在U87颅内模型中，只有瘤内直接注射NK细胞联合Bev和Iri延缓了肿瘤生长。在皮下和颅内U87模型中，静脉注射NK细胞后均检测到肿瘤浸润NK细胞。
总之，本研究中NK细胞联合Bev和Iri治疗GBM细胞的潜在疗效有限。因此，需要进一步研究以提高这种联合治疗中NK细胞的肿瘤可及性和功能强度。
展开英文摘要原文
Various combination treatments have been considered to attain the effective therapy threshold by combining independent antitumor mechanisms against the heterogeneous characteristics of tumor cells in malignant brain tumors. In this study, the natural killer (NK) cells associated with bevacizumab (Bev) plus irinotecan (Iri) against glioblastoma multiforme (GBM) were investigated. For the experimental design, NK cells were expanded and activated by K562 cells expressing the OX40 ligand and membrane-bound IL-18 and IL-21. The effects of Bev and Iri on the proliferation and NK ligand expression of GBM cells were evaluated through MTT assay and flow cytometry.
The cytotoxic effects of NK cells against Bev plus Iri-treated GBM cells were also predicted via the LDH assay in vitro . The therapeutic effect of different injected NK cell routes and numbers combined with the different doses of Bev and Iri was confirmed according to tumor size and survival in the subcutaneous (s. c) and intracranial (i.
c) U87 xenograft NOD/SCID IL-12R null mouse model. The presence of injected-NK cells in tumors was detected using flow cytometry and immunohistochemistry ex vivo . As a result, Iri was found to affect the proliferation and NK ligand expression of GBM cells, while Bev did not cause differences in these cellular processes.
However, the administration of Bev modulated Iri efficacy in the i. c U87 mouse model. NK cells significantly enhanced the cytotoxic effects against Bev plus Iri-treated GBM cells in vitro. Although the intravenous (IV) injection of NK cells in combination with Bev plus Iri significantly reduced the tumor volume in the s.
c U87 mouse model, only the direct intratumorally (IT) injection of NK cells in combination with Bev plus Iri elicited delayed tumor growth in the i. c U87 mouse model. Tumor-infiltrating NK cells were detected after IV injection of NK cells in both s. c and i. c U87 mouse models.
In conclusion, the potential therapeutic effect of NK cells combined with Bev plus Iri against GBM cells was limited in this study. Accordingly, further research is required to improve the accessibility and strength of NK cell function in this combination treatment.
论文信息
- 作者
- Tran TA、Kim YH、Duong TH、Thangaraj J、Chu TH、Jung S、Kim IY、Moon KS
- 单位
- Brain Tumor Research Laboratory, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea.South Korea
- 文献类型
- 非美国政府资助研究
- 期刊
- Frontiers in immunology2022
- 原文标识
- PubMed 36703992 · DOI 10.3389/fimmu.2022.1009484
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