title: BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties.
abstract: 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 longerin vivoafter 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.
authors.affiliation: Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Haymaker
authors.affiliation: Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA ; MD/PhD Program; University of Texas Medical School at Houston ; Houston, TX USA ; Graduate Program in Immunology; University of Texas Graduate School of Biomedical Sciences ; Houston, TX USA ; University of Texas Southwestern Medical Center; Department of Internal Medicine ; Dallas, TX USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wu
authors.affiliation: Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Graduate Program in Immunology; University of Texas Graduate School of Biomedical Sciences ; Houston, TX USA.
authors.forename: Krit
authors.initials: K
authors.lastname: Ritthipichai
authors.affiliation: Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA ; University of Texas Southwestern Medical Center; Department of Internal Medicine ; Dallas, TX USA.
authors.forename: Chantale
authors.initials: C
authors.lastname: Bernatchez
authors.affiliation: Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA.
authors.forename: Marie-Andrée
authors.initials: MA
authors.lastname: Forget
authors.affiliation: Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Lion Biotechnologies ; Tampa, FL USA.
authors.forename: Jie Qing
authors.initials: JQ
authors.lastname: Chen
authors.affiliation: Infectious Disease and Immunogenetics Section; Department of Transfusion Medicine; Clinical Center and trans-NIH Center for Human Immunology; National Institutes of Health ; Bethesda, MD USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Infectious Disease and Immunogenetics Section; Department of Transfusion Medicine; Clinical Center and trans-NIH Center for Human Immunology; National Institutes of Health ; Bethesda, MD USA ; Sidra Medical Research Hospital ; Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Surgery Branch; National Cancer Institute; National Institutes of Health ; Bethesda, MD USA ; Department of Immunology; H Lee Moffitt Cancer Center ; Tampa, FL USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marincola
authors.affiliation: Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Lion Biotechnologies ; Tampa, FL USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Lion Biotechnologies ; Tampa, FL USA ; Department of Immunology; H Lee Moffitt Cancer Center ; Tampa, FL USA.
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Radvanyi
keywords: B- and T-lymphocyte attenuator; CD8+ effector-memory; T cell survival/persistence; melanoma; tumor-infiltrating lymphocytes