ICOS and neoplasm: CpG 4/5 methylation on the other hand, that negatively correlated with ICOS mRNA expression by tumor cells and differentiation, was significantly associated with better OS in the TCGA cohort (Cox proportional hazards analysis including CpG 4/5 methylation as continuous variate: HR = 0.227 [95%CI 0.091–0.563], P = 0.001; Kaplan–Meier analysis based on an optimized cutoff: P < 0.001 (Fig. 6D)).