The Mitigating Effect of Combined Glucocorticoids with Immune Checkpoint Inhibitors on Lymphocyte Activation Gene-3...

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.