Genome-scale Pathway Flux Analysis Predicts Efficacy of anti-PD-1 Therapy in Melanoma

Abstract Background: Currently, predicting treatment efficacy to immunotherapy has been under extensive investigation. However, a putative biomarker for immunotherapy in melanoma remains to be found.Methods: Utilizing genetic data from two independent melanoma patient cohorts treated with anti-PD-1 therapy, the study described herein conducted a genome-scale pathway flux analysis (GPFA) and related statistical methods to determine whether specific pathways could be identified that are relevant to immunotherapy efficacy.Results: The analysis results highlighted three mechanisms responsible for the efficacy of immunotherapy in melanoma including 1) proper cellular functions in immune cells; 2) angiogenesis for the development and differentiation of immune cells; 3) energy metabolic remodeling to meet the activation of immune cells. Based on these discoveries, a pathway flux-based biomarker (IM.Index) was developed and assessed to validate its predictive ability with odds ratio (OR) of 3.14 (95%CI: 1.16-8.45; p=3.10E-3), sensitivity 76% and specificity 89%. The IM.Index achieved an objective response rate (ORR) of 70%. Comparison to other four putative biomarkers (TMB, NAL, neo-peptide load and cytolytic score) showed a comparative outcome with an hazard ratio (HR) of 1.83 (95%CI: 1.26-2.67; p=1.62E-3) and area under curve (AUC) of 0.82.Conclusion: These results indicate a translational potential of IM.Index, as a biomarker, for anti-PD-1 therapy in melanoma and the GPFA might pave a new path for biomarker discovery in immunotherapy.