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

被引：2341

作者：

Hugo, Willy ^{[1
,6
]}

Zaretsky, Jesse M. ^{[2
,6
]}

Sun, Lu ^{[1
,6
]}

Song, Chunying ^{[1
,6
]}

Moreno, Blanca Homet ^{[3
]}

Hu-Lieskovan, Siwen ^{[3
]}

Berent-Maoz, Beata ^{[3
]}

Pang, Jia ^{[3
]}

Chmielowski, Bartosz ^{[3
]}

Cherry, Grace ^{[3
]}

Seja, Elizabeth ^{[3
]}

Lomeli, Shirley ^{[1
,6
]}

Kong, Xiangju ^{[1
,6
]}

Kelley, Mark C. ^{[7
]}

Sosman, Jeffrey A. ^{[8
]}

Johnson, Douglas B. ^{[8
]}

Ribas, Antoni ^{[2
,3
,4
,5
,6
]}

Lo, Roger S. ^{[1
,2
,5
,6
]}

机构：

[1] Univ Calif Los Angeles, Dept Med, Div Dermatol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Surg, Div Surg Oncol, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[7] Vanderbilt Ingram Canc Ctr, Dept Surg, Nashville, TN 37232 USA

[8] Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37232 USA

来源：

CELL | 2016年 / 165卷 / 01期

关键词：

RNA-SEQ EXPERIMENTS; PD-1; BLOCKADE; EXPRESSION ANALYSIS; CTLA-4; COPY NUMBER; CANCER; GENE; PREDICTION; RESISTANCE; MUTATIONS;

D O I：

10.1016/j.cell.2016.02.065

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 MAPKinhibitor 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 antiPD- 1 response in melanoma and other cancer types.

引用

页码：35 / 44

页数：10

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