Shin and colleagues performed whole-exome sequencing of pretreatment biopsies from 23 patients with metastatic melanoma and 16 patients with metastatic colon cancer treated with anti–PD-1 therapy and identified a concomitant loss-of-function JAK1 mutation and amplification of the JAK locus in one of the patients with melanoma and a concomitant homozygous truncating JAK1 mutation and LOH at the JAK1 locus in one of the patients with colon cancer. Loss-of-function JAK1/2 mutations abrogated IFNγ-mediated signaling and subsequent upregulation of PD-L1 in patient-derived melanoma cell lines. Analysis of the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas databases revealed that truncating JAK1/2 mutations occurred in multiple types of cancer and were associated with significantly decreased overall survival in patients with melanoma or breast, prostate, and lung cancers. These findings describe the mechanism by which
loss-of-function kinase mutations induce primary resistance to anti–PD-1 therapy. For details, please see the article by Shin and colleagues on page 188.