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 (TEM) 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.
['Haymaker|Cara L|CL|', 'Wu|Richard C|RC|', 'Ritthipichai|Krit|K|', 'Bernatchez|Chantale|C|', 'Forget|Marie-Andrée|MA|', 'Chen|Jie Qing|JQ|', 'Liu|Hui|H|', 'Wang|Ena|E|', 'Marincola|Francesco|F|', 'Hwu|Patrick|P|', 'Radvanyi|Laszlo G|LG|']
tumor-infiltrating lymphocytes melanoma B- and T-lymphocyte attenuator CD8+ effector-memory T cell survival/persistence