摘要：SummaryEx vivohuman tumor models have emerged as promising, yet complex tools to study cancer immunotherapy response dynamics. Here, we present a strategy that integrates empirical data from anex vivohuman system with computational models to interpret the response dynamics of a clinically prescribed PD-1 inhibitor, nivolumab, in head and neck squamous cell carcinoma (HNSCC) biopsies (N = 50). Using biological assays, we show that drug-induced variance stratifies samples by T helper type 1 (Th1)-related pathways. We then built a systems biology network and mathematical framework of local and global sensitivity analyses to simulate and estimate antitumor phenotypes, which implicate a dynamic role for the induction of Th1-related cytokines and T cell proliferation patterns. Together, we describe a multi-disciplinary strategy to analyze and interpret the response dynamics of PD-1 blockade using heterogeneousex vivodata andin silicosimulations, which could provide researchers a powerful toolset to interrogate immune checkpoint inhibitors.Graphical AbstractDisplay OmittedHighlights•Computational strategy to study anticancer immune checkpoint blockade,ex vivo•PD-1 blockade-induced T helper type 1 (Th1) stratifies tumor biopsies,ex vivo•Systems biology links drug effect to dynamic intratumor T cell proliferation•In silicosensitivity analyses of PD-1 blockade predict Th1-induced antitumor effectsBiological Sciences; Cancer Systems Biology; Immunology; Systems Biology
