How immunological checkpoint blockade modulates tumor evolution during therapy is poorly understood. In Cell, Chan and colleagues perform whole-exome, transcriptome and TCR sequencing in 68 patients with advanced melanoma before and after therapy with antibody to the costimulatory molecule PD-1. Responders show a decrease in mutation and neoantigen load 4 weeks after initiation of therapy, whereas no single gene mutation is associated with response or resistance to therapy. Genomic contraction in responders is associated with enrichment for genes encoding molecules linked to signaling through PD-1, TCR, interferon-γ and IL-2 and the downregulation of tumor-growth pathways, such as cell-cycle regulation, mitotic division and translation. More immune-system-related genes are selectively upregulated in responders than in non-responders. Only the responders show a linear correlation between the number of expanded T cell clones and the number of neoantigens that become undetectable after therapy, which suggests that T cell clonal expansion modulates the genetic profile of the tumor and that T cells are effective in eliminating tumor cells expressing immunogenic neoantigens.

Cell (12 October 2017) 10.1016/j.cell.2017.09.028