BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties.

In a recent adoptive cell therapy (ACT) clinical trial using autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, we found an association between CD8 T cells expressing the inhibitory receptor B- and T-lymphocyte attenuator (BTLA) and clinical response. Here, we further characterized this CD8BTLA TIL subset and their CD8BTLA counterparts. We found that the CD8 BTLA TILs had an increased response to IL-2, were less-differentiated effector-memory (T) cells, and persisted longer after infusion. In contrast, CD8BTLA TILs failed to proliferate and expressed genes associated with T-cell deletion/tolerance. Paradoxically, activation of BTLA signaling by its ligand, herpes virus entry mediator (HVEM), inhibited T-cell division and cytokine production, but also activated the Akt/PKB pathway thus protecting CD8BTLA TILs from apoptosis. Our results point to a new role of BTLA as a useful T-cell differentiation marker in ACT and a dual signaling molecule that curtails T-cell activation while also conferring a survival advantage for CD8 T cells. These attributes may explain our previous observation that BTLA expression on CD8 TILs correlates with clinical response to adoptive T-cell therapy in metastatic melanoma.