The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor immunotherapy. However, the adverse side effects associated with agonist antibodies have hindered their clinical development. Here, we aimed to study the immune-related adverse events of repeated doses and long-term use of agonistic anti-4-1BB mAbs. We show that chronic activation of 4-1BB signals induced the accumulation of IFN-γ-producing PD-1⁺CD8⁺ T cells in the secondary lymphoid organs of tumor-bearing mice by increasing the number of dividing CD8⁺ T cells, which was beneficial for suppressing tumor growth in the early phase of anti-4-1BB induction. However, repeated exposure to anti-4-1BB mAbs led to granuloma development in tumor-draining lymph nodes (TDLNs) of mice due to recruitment and accumulation of macrophages via the CD8⁺ T cell-IFN-γ axis. This was accompanied by excessive lymph node swelling, which impaired the sequential activation of CD8⁺ T cells. Our data provide insights into the immune-related adverse events of long-term agonist 4-1BB antibody dosing, which should be considered during the clinical development of immunomodulating therapy.

激动性抗 4-1BB mAb 的抗肿瘤能力使其成为肿瘤免疫治疗的有吸引力的靶点。然而，与激动剂抗体相关的不良副作用阻碍了它们的临床开发。在这里，我们旨在研究重复剂量和长期使用激动性抗 4-1BB mAb 的免疫相关不良事件。我们表明，4-1BB 信号的慢性激活通过增加分裂 CD8 ⁺的数量来诱导荷瘤小鼠次级淋巴器官中产生 IFN-γ 的 PD-1 ⁺ CD8 ^{+ T 细胞的积累。}T 细胞，有利于在抗 4-1BB 诱导的早期阶段抑制肿瘤生长。^{然而，由于巨噬细胞通过 CD8 +} T 细胞-IFN-γ 轴的募集和积累，反复暴露于抗 4-1BB mAb 导致小鼠的肿瘤引流淋巴结 (TDLN) 出现肉芽肿。这伴随着过度的淋巴结肿胀，这损害了 CD8 ⁺ T 细胞的顺序激活。我们的数据提供了对长期激动剂 4-1BB 抗体给药的免疫相关不良事件的见解，在免疫调节疗法的临床开发过程中应考虑到这一点。