Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers (GC) and associated with clinical response to anti-programmed death (PD)-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in advanced MSI-H GC patients and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with anti-tumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. Additionally, increase in PD-1+ CD8+ T cells correlated with durable clinical bene fit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H GC and may inform development of strategies to enhance responsiveness.
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