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

Teofila Seremet, Alexander Koch, Yanina Jansen, Max Schreuer, Sofie Wilgenhof, Véronique Del Marmol, Danielle Liènard, Kris Thielemans, Kelly Schats, Mark Kockx, Wim Van Criekinge, Pierre G. Coulie, Tim De Meyer, Nicolas van Baren, Bart Neyns

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.