Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Seremet, Teofila; Koch, Alexander; Jansen, Yanina; Schreuer, Max; Wilgenhof, Sofie; Marmol, Véronique; Liènard, Danielle; Thielemans, Kris; Schats, Kelly; Kockx, Mark; Criekinge, Wim; Coulie, Pierre; Meyer, Tim; Baren, Nicolas; Neyns, Bart
• Is Part Of: Journal of translational medicine. Volume 14:Issue 1(2016)
• Page Start: 1
• Page End: 14
• Publication Date: 2016-12
• Subjects: Translational research -- Durable remission -- Ipilimumab -- Immunotherapy -- Metastatic melanoma; Medicine, Experimental -- Periodicals; Human experimentation in medicine -- Periodicals; Therapeutics -- Periodicals; 615.50724
• DOI: 10.1186/s12967-016-0990-x
• Languages: English
• ISSNs: 1479-5876

Abstract

Abstract 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.