Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Gwangju, Korea.
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Gwangju, Korea.
Cell Mol Immunol. 2021 Jul;18(7):1652-1661. doi: 10.1038/s41423-021-00686-9. Epub 2021 May 12.
The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγ (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.
自然杀伤 (NK) 细胞的应用是癌症免疫治疗领域中一种有前途且安全的免疫治疗方法。然而，需要联合治疗来增强 NK 细胞的效应功能和治疗效果。在这项研究中，我们研究了达雷妥尤单抗 (Dara)、硼替佐米和地塞米松 (Dvd) 联合治疗增强 NK 细胞在多发性骨髓瘤 (MM) 异种移植小鼠模型中抗肿瘤作用的潜力。我们使用 K562-OX40 配体和膜结合型 IL-18 和 IL-21，在 MM 患者外周血单个核细胞中 IL-2 和 IL-15 的存在下，扩增和激活 NK 细胞。我们用人 RPMI8226-RFP-FLuc 细胞在 NOD/SCID IL-2Rγ (NSG) 小鼠中建立了人类 MM 异种移植模型。荷瘤小鼠分为六组治疗：无治疗、扩增 NK 细胞 (eNKs)、Dara、Dara+eNKs、Dvd 和 Dvd+eNKs。Dvd 治疗通过上调 NK 细胞激活配体的表达、下调 NK 细胞抑制配体的表达和促进抗体依赖性细胞毒性，强烈增强了 eNKs 的细胞毒性。eNKs 与 Dvd 的联合使用显著延长了小鼠的存活时间，减少了肿瘤负担和血清 M 蛋白水平。此外，Dvd 预处理显著增加了 eNK 细胞的持久性和向 MM 部位的归巢。我们的研究结果表明，Dvd 治疗通过调节 MM 荷瘤小鼠的免疫反应，增强了体外扩增和激活的 NK 细胞的抗骨髓瘤作用。
