HVEM: A novel cosignaling molecule of major interest in melanoma.

Abstract

e14591 Background: Herpes Virus Entry Mediator (HVEM) is a member of the TNF superfamily, its ligation of the immunoglobulin family member B-lymphocyte and T-lymphocyte attenuator (BTLA) activates inhibitory signaling in T-cells and could play a role in evading host anti-tumor immunity. Ectopic overexpression of HVEM is associated with poor survival in some solid tumors. Our objectives were: -to evaluate HVEM expression in melanoma (MM) -to explore potential link of its overexpression with clinical outcomes -to understand the mechanisms by which HVEM was ectopically expressed in MM, and how HVEM-BTLA may play a role in MM. Methods: HVEM expression was analyzed by IHC in formalin-fixed samples of mm metastases and was correlated with OS in 130 patients. To better understand how HVEM could interfere with prognosis, relation of HVEM with its ligand BTLA was studied in the tumor and tumor microenvironment on 15 fresh metastases by flow cytometry after tumor dissociation. Bioinformatic studies based on TCGA and CCLE data combined to targeting of candidate genes by siRNA were used to investigate HVEM regulation on MM. Results: Patients with high HVEM expression on mm cells in their metastases have a significantly (p = 0.0142) poorer overall survival than those with a low expression. TCGA transcriptomic data support these results. From the mechanistic point of view, we could show that 1-HVEM expressed at the tumor cell surface interacts with BTLA expressed by tumor-infiltrated lymphocytes. 2-HVEM expression is neither linked to the mm mutational status nor inducible by IFN 3-Genes co-regulated with HVEM are associated with an aggressive gene signature 4- HVEM strongly correlate with MITF expression, MITF binds HVEM promoter, and its downregulation by siRNA results in a decrease in HVEM expression. Conclusions: A high expression of HVEM by mm metastases seems to be a pejorative prognostic marker. HVEM-BTLA interaction is a co-signaling system similar to the PD1-PDL1 one, but seem to be constitutive rather than inducible. HVEM and its co-regulated genes may constitute a signature of aggressiveness associated to MITF. High HVEM expression on mm cells may dampen anti-tumor immune responses, making HVEM and BTLA potential new targets for “checkpoint blockade” therapy.