Identification of Crucial Gene Modules Related to the Efficiency of Anti-PD-1/PD-L1 Therapy and Comprehensive Analyses of a Novel Signature Based on These Modules

Biomarker development for clinical checkpoint inhibition is still in its early stages. It is critical to determine the cause of the lack of a long-term response in patients after immune checkpoint blockade (ICB) treatment and to develop composite biomarkers or signatures to improve personalized approaches. Three modules that were significantly correlated with the immunotherapeutic response were identified. Stimulatory pathways of cellular immunity, extracellular matrix formation-related pathways, and ATP metabolism-related pathways were enriched. Two distinct transcriptional subtypes were determined. Tumor microenvironment (TME) characteristics were highly correlated with "hot" and "cold" tumors. The ICB score was significantly correlated with clinical characteristics including age, Breslow depth, Clerk level, AJCC stage, and T stage. Meanwhile, a low ICB score is characterized by increased activation of immunity, a higher level of immune infiltration, and immune molecule expression. The ICB score showed a robust ability to predict melanoma prognosis in the discovery, internal validation, and external validation cohorts. In addition, a low ICB score was linked to a higher CR/PR rate in the immunotherapeutic cohort. The ICB score could reflect the pre-existing immune features and the expression pattern of "Cold" versus "Hot" tumors in melanoma patients. Thus, it has the potential to serve as a reliable predictor of melanoma prognosis and response to ICB therapy.