R&D Division, Kyowa Kirin Co. Ltd., Shizuoka, Japan.
Department of Hematology and Oncology and.
Blood Adv. 2020 May 26;4(10):2180-2191. doi: 10.1182/bloodadvances.2020001641.
Skin-related adverse events (AEs) occur frequently in adult T-cell leukemia-lymphoma (ATL) patients treated with mogamulizumab, a humanized anti-CCR4 monoclonal antibody. This study was undertaken to elucidate the mechanisms of mogamulizumab-induced skin-related AEs. We analyzed the T-cell receptor β chain repertoire in ATL patients' peripheral blood mononuclear cells (PBMCs) before and after mogamulizumab. Skin-related AEs were present in 16 patients and were absent in 8 patients. Additionally, we included 11 patients before and after chemotherapy without mogamulizumab. Immune-related gene expression in PBMCs before and after mogamulizumab was also assessed (n = 24). Mogamulizumab treatment resulted in CCR4+ T-cell depletion, and the consequent lymphopenia provoked homeostatic CD8+ T-cell proliferation, as evidenced by increased expressions of CD8B and CD8A, which were significantly greater in patients with skin-related AEs than in those without them. We hypothesize that proliferation is driven by the engagement of self-antigens, including skin-related antigens, in the face of regulatory T-cell depletion. Together with the observed activated antigen presentation function, this resulted in T-cell diversification that was significantly greater in patients with skin-related AEs than in those without. We found that the CD8+ T cells that proliferated and diversified after mogamulizumab treatment were almost entirely newly emerged clones. There was an inverse relationship between the degree of CCR4+ T-cell depletion and increased CD8+ T-cell proliferation and diversification. Thus, lymphocyte-depleting mogamulizumab treatment provokes homeostatic CD8+ T-cell proliferation predominantly of newly emerging clones, some of which could have important roles in the pathogenesis of mogamulizumab-induced skin-related AEs.
皮肤相关不良事件（AEs）在接受莫加木单抗治疗的成人 T 细胞白血病/淋巴瘤（ATL）患者中经常发生，莫加木单抗是一种人源化抗 CCR4 单克隆抗体。本研究旨在阐明莫加木单抗诱导的皮肤相关 AEs 的机制。我们分析了莫加木单抗治疗前后 ATL 患者外周血单个核细胞（PBMC）中的 T 细胞受体β链库。16 例患者出现皮肤相关 AEs，8 例患者无皮肤相关 AEs。此外，我们还纳入了 11 例在未接受莫加木单抗化疗前后的患者。还评估了莫加木单抗治疗前后 PBMC 中的免疫相关基因表达（n = 24）。莫加木单抗治疗导致 CCR4+T 细胞耗竭，随后的淋巴细胞减少引起了 CD8+T 细胞的稳态增殖，这表现为 CD8B 和 CD8A 的表达增加，在有皮肤相关 AEs 的患者中显著高于无皮肤相关 AEs 的患者。我们假设，增殖是由自我抗原（包括皮肤相关抗原）的参与驱动的，而调节性 T 细胞的耗竭则是由于调节性 T 细胞的耗竭。与观察到的激活的抗原呈递功能一起，这导致 T 细胞多样化，在有皮肤相关 AEs 的患者中显著高于无皮肤相关 AEs 的患者。我们发现，在莫加木单抗治疗后增殖和多样化的 CD8+T 细胞几乎完全是新出现的克隆。CCR4+T 细胞耗竭的程度与 CD8+T 细胞增殖和多样化的程度呈负相关。因此，淋巴细胞耗竭的莫加木单抗治疗主要引发新出现的克隆的 CD8+T 细胞的稳态增殖，其中一些可能在莫加木单抗诱导的皮肤相关 AEs 的发病机制中发挥重要作用。
