Abstract：
: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 overall high mutational loads associate with improved survival, and tumors from responding patients are 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 up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor 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-PD-1 response in melanoma and other cancer types.
journal_name
Celljournal_title
Cellauthors
Hugo W,Zaretsky JM,Sun L,Song C,Moreno BH,Hu-Lieskovan S,Berent-Maoz B,Pang J,Chmielowski B,Cherry G,Seja E,Lomeli S,Kong X,Kelley MC,Sosman JA,Johnson DB,Ribas A,Lo RSdoi
10.1016/j.cell.2016.02.065subject
Has Abstractpub_date
2016-03-24 00:00:00pages
35-44issue
1eissn
0092-8674issn
1097-4172pii
S0092-8674(16)30215-Xjournal_volume
165pub_type
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