Brain Tumor Research Laboratory, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea.
Biomedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun, Republic of Korea.
Front Immunol. 2023 Jan 10;13:1009484. doi: 10.3389/fimmu.2022.1009484. eCollection 2022.
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 the LDH assay . 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-12Rγ mouse model. The presence of injected-NK cells in tumors was detected using flow cytometry and immunohistochemistry . 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 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.
各种联合治疗方法已经被考虑用于通过结合针对恶性脑肿瘤中肿瘤细胞异质性的独立抗肿瘤机制来达到有效的治疗阈值。在这项研究中，研究了与贝伐单抗（Bev）加伊立替康（Iri）联合治疗多形性胶质母细胞瘤（GBM）相关的自然杀伤（NK）细胞。为了进行实验设计，通过表达 OX40 配体和膜结合的 IL-18 和 IL-21 的 K562 细胞来扩增和激活 NK 细胞。通过 MTT 测定法和流式细胞术评估了 Bev 和 Iri 对 GBM 细胞增殖和 NK 配体表达的影响。通过 LDH 测定法还预测了 NK 细胞对 Bev 加 Iri 处理的 GBM 细胞的细胞毒性作用。根据皮下（s.c）和颅内（i.c）U87 异种移植 NOD/SCID IL-12Rγ 小鼠模型中的肿瘤大小和存活情况，证实了不同注射 NK 细胞途径和数量与不同剂量的 Bev 和 Iri 联合的治疗效果。通过流式细胞术和免疫组织化学检测肿瘤中注射的 NK 细胞的存在。结果发现，Iri 影响 GBM 细胞的增殖和 NK 配体表达，而 Bev 不会引起这些细胞过程的差异。然而，Bev 的给药调节了 Iri 在 i.c U87 小鼠模型中的功效。NK 细胞显著增强了对 Bev 加 Iri 处理的 GBM 细胞的细胞毒性作用。虽然 NK 细胞联合 Bev 加 Iri 的静脉内（IV）注射显著降低了 s.c U87 小鼠模型中的肿瘤体积，但仅直接肿瘤内（IT）注射 NK 细胞联合 Bev 加 Iri 才导致 i.c U87 小鼠模型中的肿瘤生长延迟。在 s.c 和 i.c U87 小鼠模型中均检测到 NK 细胞静脉内注射后的肿瘤浸润 NK 细胞。总之，在这项研究中，NK 细胞联合 Bev 加 Iri 对 GBM 细胞的潜在治疗效果有限。因此，需要进一步研究以提高 NK 细胞在这种联合治疗中的可及性和功能强度。
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