ICOS and ICOS ligand: expression patterns and outcomes in oncology patients

Abstract

Background: Inducible T-cell co-stimulator (ICOS) and its ligand (ICOSL) form a complex, two-faced immune machinery that can lead to both immune stimulation and inhibition. Objective: We explored ICOS transcriptomic expression patterns and their relationship with other checkpoints and with outcomes in patients with advanced/metastatic cancers. Design: This was a retrospective cohort study. Methods: RNA expression for ICOS and other immune checkpoints was quantified by RNA sequencing and stratified by rank values into high (75–100 percentiles) and low (0–24 percentiles). Fischer’s exact tests were used for univariate analyses to evaluate independent predictors of ICOS high and logistic regression was used for multivariate analyses. Progression-free survival (PFS) and overall survival (OS) for ICOS high versus not high expression were evaluated using the log-rank test (Kaplan–Meier analysis) and Cox proportional hazards. Results: High ICOS (⩾75 percentile RNA rank) was present in 14% of 514 cancers and independently associated with high PD-1 ( p = 0.025), PD-L1 ( p < 0.0001), and CTLA-4 RNA expression ( p < 0.0001) and with patients not having colorectal cancer ( p = 0.0009; multivariate analysis). Patterns of ICOS and ICOSL expression varied between and within tumor types. For 217 patients receiving immune checkpoint inhibitors (ICIs), there were no significant differences in PFS or OS between patients with ICOS high versus not-high expression (multivariate analysis). In 272 immunotherapy-naïve patients, OS was also similar between patients with ICOS high versus not-high expression ( p = 0.91). Conclusion: High ICOS expression was not a prognostic marker and did not independently predict outcomes after ICIs. Variable expression of ICOS/ICOSL between tumors and association of high ICOS with high PD-1, PD-L1, and CTLA-4 suggest that individual tumor immunomic analysis may be required for optimized patient selection in clinical trials targeting the ICOS/ICOSL system, especially when given in combination with ICIs. Trial registration: UCSD_PREDICT, NCT02478931.