Cross-platform comparison of independent datasets identifies an immune signature associated with improved survival in metastatic melanoma

Abstract

Platform and study differences in prognostic signatures from metastatic melanoma (MM) gene expression reports often hinder consensus arrival. We performed survival/outcome-based pairwise comparisons of three independent MM gene expression profiles using the threshold-free algorithm rank-rank hypergeometric overlap analysis (RRHO). We found statistically significant overlap for genes overexpressed in favorable outcome (FO) groups, but no overlap for poor outcome (PO) groups. This “favorable outcome signature” (FOS) of 228 genes coinciding on all three overlapping gene lists showed immune function predominated in FO MM. Surprisingly, specific cell signature-enrichment analysis showed B cell-associated genes enriched in FO MM, along with T cell-associated genes. Higher levels of B and T cells (p<0.05) and their relative proximity (p<0.05) were detected in FO-to-PO tumor comparisons from an independent MM patients cohort. Finally, expression of FOS in two independent Stage III MM tumor datasets correctly predicted clinical outcome in 12/14 and 44/70 patients using a weighted gene voting classifier (area under the curve values 0.96 and 0.75, respectively). This RRHO-based, cross-study analysis emphasizes the RRHO approach power, confirms T cells relevance for prolonged MM survival, supports a favorable role for B cells in anti-melanoma immunity, and suggests B cells potential as means of intervention in melanoma treatment.

Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib

“…Genomic signatures seem to play a key role in patient outcomes in BRAF V600 -mutated melanoma. Increased tumor immune gene expression (both activating and suppressive genes) and low cellcycle gene expression are associated with longer PFS in vemurafenib-treated patients, consistent with what has been shown previously with other treatments in melanoma (9)(10)(11)(12)16). In contrast, increased expression of cell-cycle genes and low immune-related gene expression was associated with shorter PFS in patients treated with vemurafenib monotherapy, while comparable PFS outcomes for cell-cycle and immune signatures were seen in patients treated with cobimetinib and vemurafenib.…”

“…The observation of better PFS associated with the immune signature is consistent with previous observations. Pretreatment immune context has previously been shown to be associated with outcomes in patients with metastatic melanoma (9)(10)(11)(12)16) as well as in other cancer types (17). However, these signatures were not developed in the context of molecularly targeted therapy.…”

“…Although prognostic and predictive gene signatures have previously been identified in patients with metastatic melanoma, they have not been developed in the context of targeted therapy (8)(9)(10)(11)(12). The success of targeted therapy in patients with metastatic melanoma highlights the need for additional biomarkers to identify subsets of patients who are likely to derive long-term clinical benefit from BRAF inhibitor monotherapy or combined BRAF and MEK inhibition.…”

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

“…In general, a strong immunological host response is considered to be prognostically favorable. Lardone et al compared three independent gene expression studies and found a common immune gene signature of T cell-associated genes among favorable outcome patients with stage III-IV CMM [ 16 ]. Several studies have demonstrated that presence of tumor infiltrating lymphocytes (TILs) in primary tumors is associated with a better clinical outcome [ 17 , 18 ].…”

Cold physical plasma selects for specific T helper cell subsets with distinct cells surface markers in a caspase‐dependent and NF‐κB‐independent manner

“…Lymphocytes, for example, T helper cells (T H cells) can foster cytotoxic T cell antitumor activity and vividly interact with antigen presenting cells in or near the tumor microenvironment to mount cellular and humoral immune responses, often also forming local tertiary lymphoid structures (TLS) . Lymphocytes can be categorized into naïve cells, that have not encountered their antigen yet, and effector/memory cells.…”