title: Indicators of responsiveness to immune checkpoint inhibitors.
abstract: Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression. Currently, it is impossible to predict therapeutic response. Here, we report the first proteomic and histone epigenetic analysis of patient metastatic melanoma tumors taken prior to checkpoint blockade, which revealed biological signatures that can stratify patients as responders or non-responders. Furthermore, our findings provide evidence of mesenchymal transition, a known mechanism of immune-escape, in non-responding melanoma tumors. We identified elevated histone H3 lysine (27) trimethylation (H3K27me3), decreased E-cadherin, and other protein features indicating a more mesenchymal phenotype in non-responding tumors. Our results have implications for checkpoint inhibitor therapy as patient specific responsiveness can be predicted through readily assayable proteins and histone epigenetic marks, and pathways activated in non-responders have been identified for therapeutic development to enhance responsiveness.
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Shields
authors.affiliation: Departments of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Fade
authors.initials: F
authors.lastname: Mahmoud
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Taylor
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Byrum
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Deepanwita
authors.initials: D
authors.lastname: Sengupta
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Koss
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Baldini
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Ransom
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Cline
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Mackintosh
authors.affiliation: Departments of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Ricky D
authors.initials: RD
authors.lastname: Edmondson
authors.affiliation: Departments of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Shalin
authors.affiliation: Departments of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA. ajtackett@uams.edu.|Departments of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas, 72205, USA. ajtackett@uams.edu.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Tackett
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D042421:Histone Code; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology*; D020543:Proteome / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D061026:Programmed Cell Death 1 Receptor; D020543:Proteome