Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles
Weiyu Ye, Anna Olsson‐Brown, Robert Watson, Vincent Cheung, Robert D. Morgan, Isar Nassiri, Rosalin Cooper, Chelsea Taylor, Umair Akbani, Oliver Brain, Rubeta Matin, Nicholas Coupe, Mark R. Middleton, Mark Coles, Joseph J. Sacco, Miranda Payne, Benjamin P. Fairfax
Abstract
Abstract Background Immune checkpoint blockers (ICBs) activate CD8 + T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. Methods Retrospective evaluation of irAEs on survival was performed across primary ( N = 144) and secondary ( N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8 + T cells was sequenced and differential gene expression according to irAE development assessed. Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached ( P = 2.8 × 10 −6 ). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8 + T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.