title: Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.
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.
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Willy
authors.initials: W
authors.lastname: Hugo
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Zaretsky
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Song
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Blanca Homet
authors.initials: BH
authors.lastname: Moreno
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Siwen
authors.initials: S
authors.lastname: Hu-Lieskovan
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Berent-Maoz
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Pang
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Cherry
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Seja
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Lomeli
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Xiangju
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Surgery, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelley
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1662, USA; Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA 90095-1662, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1662, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA. Electronic address: rlo@mednet.ucla.edu.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D024682:BRCA2 Protein / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D059467:Transcriptome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab