title: Transcriptional Mechanisms of Resistance to Anti-PD-1 Therapy.
abstract: Purpose:To explore factors associated with response and resistance to anti-PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response.Materials and Methods:Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy.Results:The melanoma was driven by biallelic inactivation ofNF1All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with overexpression of genes associated with extracellular matrix and neutrophil function.Conclusions:Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti-PD-1 outcomes.Clin Cancer Res; 23(12); 3168-80. ©2017 AACRSee related commentary by Wilmott et al., p. 2921.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Ascierto
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Alvin
authors.initials: A
authors.lastname: Makohon-Moore
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Lipson
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.|Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Tracee L
authors.initials: TL
authors.lastname: McMiller
authors.affiliation: The Lowe Family Genomics Core, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Berger
authors.affiliation: The Lowe Family Genomics Core, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Jinshui
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Genevieve J
authors.initials: GJ
authors.lastname: Kaunitz
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Tricia R
authors.initials: TR
authors.lastname: Cottrell
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Kohutek
authors.affiliation: Oncology Bioinformatics Core, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.|Laboratory of System Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Favorov
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Riaz
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Oncology Bioinformatics Core, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.|Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.|Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.affiliation: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. stopali1@jhmi.edu iacobuzc@mskcc.org.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. stopali1@jhmi.edu iacobuzc@mskcc.org.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
mesh_terms: D060965:Clonal Evolution / Q000276:immunology; D056915:DNA Copy Number Variations / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D009362:Neoplasm Metastasis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology*; D016896:Treatment Outcome; D000073359:Exome Sequencing
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor