Unmasking PD-1 Resistance by Next-Generation Sequencing

Monoclonal antibodies that inhibit the programmed death 1 (PD-1)–programmed death ligand 1 (PD-L1) pathway are clinically active against a broad range of tumors; however, even the most susceptible tumors (e.g., melanoma) respond less than half the time because of innate resistance. In this issue of the Journal, Zaretsky et al.1 describe the use of whole-exome sequencing to identify mechanisms of acquired immune resistance in tumors from patients with melanoma who had a relapse after more than 6 months of tumor response to treatment with pembrolizumab. Tumor regression after PD-1–PD-L1 blockade is presumed to be mediated by the activation of tumor-infiltrating . . .