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- Title
Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients.
- Authors
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
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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).<bold>Results: </bold>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.<bold>Conclusion: </bold>Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.
- Subjects
IPILIMUMAB; IMMUNOTHERAPY; IMMUNOHISTOCHEMISTRY; RNA sequencing; METHYLATION; THERAPEUTICS
- Publication
Journal of Translational Medicine, 2016, Vol 14, p1
- ISSN
1479-5876
- Publication type
journal article
- DOI
10.1186/s12967-016-0990-x