Inoue Yusuke, Tenshin Hirofumi, Teramachi Jumpei, Sumitani Ryohei, Oda Asuka, Maeda Yusaku, Oura Masahiro, Sogabe Kimiko, Maruhashi Tomoko, Takahashi Mamiko, Fujii Shiro, Nakamura Shingen, Miki Hirokazu, Hara Tomoyo, Endo Itsuro, Kagawa Kumiko, Ozaki Shuji, Hiasa Masahiro, Harada Takeshi, Abe Masahiro
Department of Medical Technology, Tokushima University Hospital, Tokushima, Japan.
Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
Cancer Sci. 2025 Feb;116(2):559-563. doi: 10.1111/cas.16401. Epub 2024 Nov 18.
Multiple myeloma (MM) cells and osteoclasts (OCs) activate with each other to cause drug resistance. Human Th1-like Vγ9Vδ2 (γδ) T cells, important effectors against tumors, can be expanded and activated ex vivo by the aminobisphosphonate zoledronic acid in combination with IL-2. We previously reported that the expanded γδ T cells effectively targeted and killed OCs as well as MM cells. Because the expanded γδ T cells expressed CD16 on their surface, we investigated the utilization of the expanded γδ T cells for antibody-dependent cellular cytotoxicity (ADCC). Although the expanded γδ T cells alone induced cell death in MM cell lines, the addition of the anti-SLAMF7 monoclonal antibody elotuzumab (ELO) further enhanced their cytotoxic activity only against SLAMF7-expressing MM cell lines and primary MM cells. Intriguingly, ELO was also able to enhance γδ T cell-induced cell death against OCs cultured alone, and against both MM cells and OCs in their coculture settings. SLAMF7 was found to be highly expressed in OCs differentiated in vitro from monocytes by receptor activator of nuclear factor-κ B ligand and M-CSF, although monocytes only marginally expressed SLAMF7. These results demonstrate that SLAMF7 is highly expressed in both MM cells and OCs, and that the ex vivo-expanded γδ T cells can exert ELO-mediated ADCC against SLAMF7-expressing MM cells and OCs besides their direct cytotoxic activity. Further study is warranted for the innovative utilization of γδ T cells.
多发性骨髓瘤（MM）细胞与破骨细胞（OC）相互激活导致耐药。人Th1样Vγ9Vδ2（γδ）T细胞是抗肿瘤的重要效应细胞，可通过氨基双膦酸盐唑来膦酸联合白细胞介素-2在体外扩增和激活。我们之前报道过，扩增后的γδ T细胞能有效靶向并杀死OC以及MM细胞。由于扩增后的γδ T细胞表面表达CD16，我们研究了扩增后的γδ T细胞在抗体依赖性细胞毒性（ADCC）中的应用。虽然单独的扩增γδ T细胞能诱导MM细胞系发生细胞死亡，但添加抗信号淋巴细胞激活分子家族成员7（SLAMF7）单克隆抗体埃罗妥珠单抗（ELO）仅能进一步增强其对表达SLAMF7的MM细胞系和原发性MM细胞的细胞毒性活性。有趣的是，ELO还能增强γδ T细胞诱导的对单独培养的OC以及共培养环境中MM细胞和OC的细胞死亡。虽然单核细胞仅少量表达SLAMF7，但发现通过核因子-κB受体激活剂配体和巨噬细胞集落刺激因子在体外从单核细胞分化而来的OC中SLAMF7高度表达。这些结果表明，SLAMF7在MM细胞和OC中均高度表达，并且体外扩增的γδ T细胞除了具有直接细胞毒性活性外，还能对表达SLAMF7的MM细胞和OC发挥ELO介导的ADCC作用。γδ T细胞的创新应用值得进一步研究。
