Department for Health, University of Bath, United Kingdom.
Department for Health, University of Bath, United Kingdom; School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom.
Brain Behav Immun. 2024 May;118:468-479. doi: 10.1016/j.bbi.2024.03.023. Epub 2024 Mar 17.
Chronic lymphocytic leukaemia (CLL) is characterised by the clonal proliferation and accumulation of mature B-cells and is often treated with rituximab, an anti-CD20 monoclonal antibody immunotherapy. Rituximab often fails to induce stringent disease eradication, due in part to failure of antibody-dependent cellular cytotoxicity (ADCC) which relies on natural killer (NK)-cells binding to rituximab-bound CD20 on B-cells. CLL cells are diffusely spread across lymphoid and other bodily tissues, and ADCC resistance in survival niches may be due to several factors including low NK-cell frequency and a suppressive stromal environment that promotes CLL cell survival. It is well established that exercise bouts induce a transient relocation of NK-cells and B-cells into peripheral blood, which could be harnessed to enhance the efficacy of rituximab in CLL by relocating both target and effector cells together with rituximab in blood. In this pilot study, n = 20 patients with treatment-naïve CLL completed a bout of cycling 15 % above anaerobic threshold for ∼ 30-minutes, with blood samples collected pre-, immediately post-, and 1-hour post-exercise. Flow cytometry revealed that exercise evoked a 254 % increase in effector (CD3CD56CD16) NK-cells in blood, and a 67 % increase in CD5CD19CD20 CLL cells in blood (all p < 0.005). NK-cells were isolated from blood samples pre-, and immediately post-exercise and incubated with primary isolated CLL cells with or without the presence of rituximab to determine specific lysis using a calcein-release assay. Rituximab-mediated cell lysis increased by 129 % following exercise (p < 0.001). Direct NK-cell lysis of CLL cells - independent of rituximab - was unchanged following exercise (p = 0.25). We conclude that exercise improved the efficacy of rituximab-mediated ADCC against autologous CLL cells ex vivo and propose that exercise should be explored as a means of enhancing clinical responses in patients receiving anti-CD20 immunotherapy.
慢性淋巴细胞白血病（CLL）的特征是成熟 B 细胞的克隆性增殖和积累，通常用利妥昔单抗（一种抗 CD20 单克隆抗体免疫疗法）治疗。利妥昔单抗常常不能诱导严格的疾病消除，部分原因是抗体依赖性细胞毒性（ADCC）失败，ADCC 依赖于自然杀伤（NK）细胞结合 B 细胞上的利妥昔单抗结合的 CD20。CLL 细胞在淋巴样和其他身体组织中广泛扩散，在生存龛中的 ADCC 抵抗可能是由于多种因素造成的，包括 NK 细胞频率低和促进 CLL 细胞存活的抑制性基质环境。运动诱导 NK 细胞和 B 细胞短暂迁移到外周血中已经得到充分证实，这可以通过将 NK 细胞和 B 细胞与利妥昔单抗一起转移到血液中来增强利妥昔单抗在 CLL 中的疗效。在这项初步研究中，n=20 例初治 CLL 患者完成了 15%以上无氧阈值的骑行运动，持续约 30 分钟，在运动前、运动后即刻和运动后 1 小时采集血样。流式细胞术显示，运动引起血液中效应（CD3CD56CD16）NK 细胞增加 254%，血液中 CD5CD19CD20 CLL 细胞增加 67%（均 p<0.005）。从运动前和运动后即刻的血样中分离出 NK 细胞，并与或不与利妥昔单抗一起孵育原代分离的 CLL 细胞，用钙黄绿素释放测定法确定特异性裂解。运动后利妥昔单抗介导的细胞裂解增加了 129%（p<0.001）。运动后直接 NK 细胞对 CLL 细胞的裂解（不依赖于利妥昔单抗）没有变化（p=0.25）。我们得出结论，运动提高了利妥昔单抗介导的针对自体 CLL 细胞的 ADCC 疗效，并提出应探索运动作为增强接受抗 CD20 免疫治疗患者临床反应的一种手段。
