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Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients

  • Seremet, Teofila
  • Koch, Alexander
  • Jansen, Yanina
  • Schreuer, Max
  • Wilgenhof, Sofie
  • Del Marmol, Véronique
  • Liènard, Danielle
  • Thielemans, Kris
  • Schats, Kelly
  • Kockx, Mark
  • Van Criekinge, Wim
  • Coulie, Pierre G
  • De Meyer, Tim
  • van Baren, Nicolas
  • Neyns, Bart
Publication Date
Jan 01, 2016
Ghent University Institutional Archive
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Background: 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. Methods: 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). Results: 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. Conclusion: Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.

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