The Mitigating Effect of Combined Glucocorticoids with Immune Checkpoint Inhibitors on Lymphocyte Activation Gene‐3 and Programmed Death‐1 Expression

Cancer immunotherapy with immune checkpoint inhibitors (ICI) shows promising therapeutic efficacy but can cause immune-related adverse events (irAEs). Glucocorticoids (GCs) are commonly employed with ICI to mitigate irAEs. We had found previously that GCs upregulate significantly the inhibitory molecule, lymphocyte activation gene-3 (LAG-3) in peripheral blood and synovial fluid mononuclear cells (PBMCs and SFMCs, respectively). Here, we investigated the effect of GCs combined with ICI on LAG-3 and programmed death-1 (PD-1) expression in SFMCs of 32 inflammatory arthritis patients and PBMCs of 15 healthy controls. GC+Pembrolizumab (PEM, anti-PD-1) induced IL-10 and suppressed IFN-γ, TNF-α, and IL-17A mRNA expressions compared with PEM alone in PBMCs and SFMCs. PBMC proliferation was markedly inhibited by GC+PEM (3.5 ± 0.7%, p < 0.0006) compared with PEM alone (26.2 ± 6.5%). GC+PEM increased the CD4⁺LAG-3⁺ T cells (4.9±1.2%, p < 0.03) compared with PEM alone (0.9 ± 0.3%), but did not affect CD4⁺PD-1⁺ T cells. The effect of the drugs on synovial cells revealed that GC+PEM remarkably increased the CD14⁺LAG-3⁺ cells in SFMCs (10.4 ± 2.0%, p < 0.0001) compared with PEM alone (0.6 ± 0.2%), but not the CD14⁺PD-1⁺ cells. Thus, GC combined with ICI might exhibit contrasting activity via upregulation of CD4⁺LAG-3⁺ T and CD14⁺LAG-3⁺ cells in circulation and synovial milieu, respectively, possibly interfering with the ICI activity.