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 CD8(+)BTLA(+) TIL subset and their CD8(+)BTLA(−) counterparts. We found that the CD8(+) BTLA(+) TILs had an increased response to IL-2, were less-differentiated effector-memory (T(EM)) cells, and persisted longer in vivo after infusion. In contrast, CD8(+)BTLA(−) 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 CD8(+)BTLA(+) 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.