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

Abstract

BackgroundIpilimumab (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.MethodsFreshly 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).ResultsPatients 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.ConclusionCombined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0990-x) contains supplementary material, which is available to authorized users.

Presence of immune cells, low tumor proliferation and wild type BRAF mutation status is associated with a favourable clinical outcome in stage III cutaneous melanoma

“…Today there are no established predictive markers for immunotherapy with antibodies against CTLA-4 and PD-1 in CMM. However, there are several studies indicating that both preexistence and a post-treatment increase in intratumoral CD8+ T cells in metastatic CMM may predict response to therapy with CTLA-4 and PD-1 blockade [ 40 – 42 ]. We found a significant positive correlation between CD8+ and FOXP3+ T-cells, in concordance with another recent study on a cohort including stage III CMM patients with sentinel lymph node metastases [ 43 ].…”

Prognostic Significance of Tumor-Infiltrating B Cells and Plasma Cells in Human Cancer

“…On the other hand, coordinated antibody and T-cell responses to tumor antigens such as NY-ESO-1 are well documented in cancer (2,3), revealing that the Th1/Th2 paradigm is not absolute. Moreover, cancer immunotherapies such as vaccines and checkpoint blockade enhance both T-cell and B-cell responses (4,5), which is typically viewed as a desirable outcome. Furthermore, in autoimmunity and allograft rejection, cooperation between B cells and T cells is well established and indeed associated with the most aggressive immune responses against tissues (6,7).…”

Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response

“…In addition, in colorectal cancer, PD-L1 expression is associated with CpG island hypermethylation in a subpopulation of BRAF V600E carriers with high infiltration of CD3 + T cells [182]. Moreover, in metastatic melanoma patients treated with CTLA-4 blockers, responders and non-responders have a differential pattern of DNA methylation in specific genes of the nervous system development and neuron differentiation pathways [88]. Because neuron and melanocytes have precursor cells of neural crest origin, these results suggest a process of de-differentiation of the transformed melanocytes refractory to ICB treatment.…”