The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy

The regulation of the immune system is controlled by many cell surface receptors. A prominent representative is the ‘molecular switch’ HVEM (herpes virus entry mediator) that can activate either proinflammatory or inhibitory signaling pathways. HVEM ligands belong to two distinct families: the TNF-related cytokines LIGHT and lymphotoxin-α, and the Ig-related membrane proteins BTLA and CD160. HVEM and its ligands have been involved in the pathogenesis of various autoimmune and inflammatory diseases, but recent reports indicate that this network may also be involved in tumor progression and resistance to immune response. Here we summarize the recent advances made regarding the knowledge on HVEM and its ligands in cancer cells, and their potential roles in tumor progression and escape to immune responses. Blockade or enhancement of these pathways may help improving cancer therapy.

► HVEM has five distinct ligands: LIGHT and LTα in the TNF family and BTLA, CD160 and herpesvirus gD in the Ig family.
► HVEM and its ligands are involved in the pathogenesis of autoimmune, inflammatory and neoplastic diseases.
► Recently described alterations of the HVEM network in tumor cells and microenvironment are discussed.
► Models for targeting these co-signaling molecules in cancer therapy are proposed.