Systematic Assessment of Transcriptomic Biomarkers for Immune Checkpoint Blockade Response in Cancer Immunotherapy

SIMPLE SUMMARY: The aim of our study was to evaluate the predictive performance of transcriptomic biomarkers to immune response. The study collected 22 transcriptomic biomarkers and constructed multiple benchmark datasets to evaluate their predictive performance of immune checkpoint blockade (ICB) response in pre-treatment patients with distinct ICB agents in diverse cancers. We found “Immune-checkpoint molecule” biomarkers PD-L1, PD-L2, CTLA-4 and IMPRES and the “Effector molecule” biomarker CYT showed significant associations with ICB response and clinical outcomes. These immune-checkpoint biomarkers and another immune effector IFN-gamma presented predictive ability in melanoma, urothelial cancer and clear cell renal-cell cancer. Interestingly, for anti-PD-1 therapy and anti-CTLA-4 therapy, the top-performing response biomarkers were usually mutually exclusive even though in the same biomarker category and most of biomarkers with outstanding predictive power were observed in patients with combined anti-PD-1 and anti-CTLA-4 therapy. ABSTRACT: Background: Immune checkpoint blockade (ICB) therapy has yielded successful clinical responses in treatment of a minority of patients in certain cancer types. Substantial efforts were made to establish biomarkers for predicting responsiveness to ICB. However, the systematic assessment of these ICB response biomarkers remains insufficient. Methods: We collected 22 transcriptome-based biomarkers for ICB response and constructed multiple benchmark datasets to evaluate the associations with clinical response, predictive performance, and clinical efficacy of them in pre-treatment patients with distinct ICB agents in diverse cancers. Results: Overall, “Immune-checkpoint molecule” biomarkers PD-L1, PD-L2, CTLA-4 and IMPRES and the “Effector molecule” biomarker CYT showed significant associations with ICB response and clinical outcomes. These immune-checkpoint biomarkers and another immune effector IFN-gamma presented predictive ability in melanoma, urothelial cancer (UC) and clear cell renal-cell cancer (ccRCC). In non-small cell lung cancer (NSCLC), only PD-L2 and CTLA-4 showed preferable correlation with clinical response. Under different ICB therapies, the top-performing biomarkers were usually mutually exclusive in patients with anti-PD-1 and anti-CTLA-4 therapy, and most of biomarkers presented outstanding predictive power in patients with combined anti-PD-1 and anti-CTLA-4 therapy. Conclusions: Our results show these biomarkers had different performance in predicting ICB response across distinct ICB agents in diverse cancers.