Anti-PD-L1 antibodies exacerbate arthritis and pain via increased production of CXCL8/IL-8 and FGF9 in synovial fibroblasts

Immune checkpoint inhibitors (ICIs) in cancer therapy are challenged for immune-related adverse events (irAEs), such as inflammatory arthritis induced by ICI therapy (ICI-arthritis) and exacerbation of rheumatoid arthritis (RA). As well as activating T cells by inhibiting programmed cell death protein 1 (PD-1)/ programmed death ligand 1 (PD-L1) signal, anti-PD-L1 antibody (αPD-L1 ab) activate intracellular pathway through PD-L1 binding. However, the effects of αPD-L1 ab on synovial fibroblasts, which are important in the pathogenesis of arthritis, are unknown. To assess the effect of αPD-L1 ab on synovial fibroblasts, fibroblast-like synoviocytes (RA-FLS) were collected from two RA patients and stimulated with tumor necrosis factor (TNF)-α. The cells were then stimulated with αPD-L1 ab (BioXCell) or Ctrl IgG for 24 h and total RNA was collected. The obtained total RNA was subjected to RNA-seq to examine gene expression comprehensively.

癌症治疗领域中，免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）常面临免疫相关不良反应（immune-related adverse events, irAEs）的困境，这类不良反应包括免疫检查点抑制剂治疗诱导的炎性关节炎（ICI-arthritis）以及类风湿关节炎（rheumatoid arthritis, RA）的病情恶化。抗PD-L1抗体（αPD-L1 ab）除可通过抑制程序性死亡蛋白1（programmed cell death protein 1, PD-1）/程序性死亡配体1（programmed death ligand 1, PD-L1）信号通路活化T细胞外，还可通过结合PD-L1激活细胞内信号通路。然而，抗PD-L1抗体对滑膜成纤维细胞的影响尚不明确——这类细胞在关节炎的发病机制中具有关键作用。为评估抗PD-L1抗体对滑膜成纤维细胞的作用，本研究从2名类风湿关节炎患者体内分离得到成纤维样滑膜细胞（fibroblast-like synoviocytes, RA-FLS），并以肿瘤坏死因子α（tumor necrosis factor, TNF-α）进行刺激。随后将细胞分别用抗PD-L1抗体（αPD-L1 ab，购自BioXCell）或对照IgG（Ctrl IgG）处理24小时，收集总RNA。将提取的总RNA进行RNA测序（RNA-seq），以全面分析基因表达谱。