Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, CHEMOTHERAPY, CAMRELIZUMAB, THERAPY, PLACEBO, Humans, Receptor, Notch1, Esophageal Neoplasms, Antibodies, Monoclonal, Humanized, Esophageal Squamous Cell Carcinoma, Mutation, Animals, Biomarkers, Tumor, Mice, Female, Male, Middle Aged, Survival Analysis, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3211 Oncology and carcinogenesis

Abstract:

PURPOSE: Although multiple agents targeting PD-1 have been approved as second-line treatment for esophageal squamous cell carcinoma (ESCC), only a fraction of patients derive long-term survival. Hence, reliable predictive biomarkers are urgently needed. METHODS: Comprehensive tumor genomic profiling and transcriptome sequencing were performed on samples from the RATIONALE-302 study. We also conducted single-cell RNA sequencing analysis on Notch1 knockdown ESCC murine models to further explore the potential molecular mechanisms underlying anti-PD-1 benefit. RESULTS: We identified NOTCH1 mutation as a potential predictive biomarker for longer overall survival (OS) with tislelizumab versus chemotherapy (18.4 months v 5.3 months; hazard ratio, 0.35 [95% CI, 0.17 to 0.71]). At the transcriptional level, type I IFN (IFN-I)/toll-like receptor expression signatures were positively associated with OS benefit of tislelizumab, whereas B-cell and neutrophil signatures predicted unfavorable OS. Exploratory analyses showed that the presence of NOTCH1 mutation correlated with enrichment of IFN-I signatures and reduced infiltration of B cells and neutrophils. In murine models, comparative single-cell transcriptome analyses further revealed that Notch1 deficiency facilitated a more immunologically activated tumor microenvironment which potentiated anti-PD-1 treatment. CONCLUSION: Our data provide novel insights for anti-PD-1 treatment selection using NOTCH1 mutations and may provide a rationale for combination therapy in ESCC.