Among the growing family of inhibitory receptors, the B and T lymphocyte attenuator (BTLA), which interacts with herpes virus entry mediator (HVEM), inhibits T-cell proliferation and cytokine production [24, 25], suggesting that BTLA might be an interesting target in immunotherapy . Naive human CD8+ T cells express high levels of BTLA, which is downregulated upon CD8 differentiation. However, BTLA is not downregulated in melanoma specific CD8+ T cells and remains susceptible to functional inhibition upon HVEM ligation. HVEM is frequently expressed on melanoma cells, suggesting that the BTLA/HVEM pathway might play a role in the inhibition of efficient immune responses against cancer. Preventing/targeting the BTLA/HVEM interaction can reverse the inhibitory functions of BTLA, thus triggering the immune response against cancer. Additionally, in vitro studies using antibodies to block binding of BTLA to HVEM led to increased melanoma specific CD8+ effector T-cells proliferation and enhanced cytokines production [27–29].