Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma

作者：Willy Hugo, J. Zaretsky, Lu Sun, Chunying Song, B. H. Moreno, S. Hu-Lieskovan, B. Berent-Maoz, Jia Pang, B. Chmielowski, Grace Cherry, E. Seja, Shirley H. Lomeli, X. Kong, M. Kelley, J. Sosman, Douglas B. Johnson, A. Ribas, R. Lo · 发表于：Cell · 年份：2016 · DOI：10.1016/j.cell.2016.02.065 · 被引用次数：3059 · 研究领域：Biology、Medicine

SUMMARY PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that, while overall high mutational loads associate with improved survival both in responding and non-responding patients, responding tumors are specifically enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES or Innate anti-PD-1 Resistance) indicating concurrent upexpression of genes involved in the regulation of mesenchymal transition, cell adhesion, ECM remodeling, angiogenesis and wound-healing. Notably, MAPK-targeted therapy (MAPKi) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPKi resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD1 response in melanoma and other cancer types.