title: Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients.
abstract: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies.
  
  
  
  Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq).
  
  
  
  Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8(+) and PD-L1(+) cells than NB tumors. B cells (CD20(+)) and macrophages (CD163(+)) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples.
  
  
  
  Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.
authors.affiliation: Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium. teofila.caplanusi@uzbrussel.be.|Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium. teofila.caplanusi@uzbrussel.be.
authors.forename: Teofila
authors.identifier: 0000-0002-3789-6256
authors.initials: T
authors.lastname: Seremet
authors.affiliation: Department of Mathematical Modelling, Statistics and Bioinformatics Bionformatics Institute Ghent (BIG N2N), Ghent University, Ghent, Belgium.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Yanina
authors.initials: Y
authors.lastname: Jansen
authors.affiliation: Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Max
authors.initials: M
authors.lastname: Schreuer
authors.affiliation: Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Wilgenhof
authors.affiliation: Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Del Marmol
authors.affiliation: Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Danielle
authors.initials: D
authors.lastname: Liènard
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.affiliation: HistoGeneX Laboratories, Campus Middelheim, Antwerp, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Schats
authors.affiliation: HistoGeneX Laboratories, Campus Middelheim, Antwerp, Belgium.
authors.forename: Mark
authors.initials: M
authors.lastname: Kockx
authors.affiliation: Department of Mathematical Modelling, Statistics and Bioinformatics Bionformatics Institute Ghent (BIG N2N), Ghent University, Ghent, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Criekinge
authors.affiliation: de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
authors.affiliation: Department of Mathematical Modelling, Statistics and Bioinformatics Bionformatics Institute Ghent (BIG N2N), Ghent University, Ghent, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: De Meyer
authors.affiliation: de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.|Ludwig Institute for Cancer Research, Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: van Baren
authors.affiliation: Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D003710:Demography; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D005629:Frozen Sections; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007167:Immunotherapy; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016612:Paraffin Embedding; D012074:Remission Induction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000074324:Ipilimumab
keywords: Durable remission; Immunotherapy; Ipilimumab; Metastatic melanoma; Translational research