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Oncoimmunology. 2015 Mar 16;4(8):e1014246. eCollection 2015 Aug.

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

Author information

1
Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA.
2
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.
3
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.
4
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.
5
Department of Melanoma Medical Oncology; The University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Lion Biotechnologies ; Tampa, FL USA.
6
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.
7
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.
8
Surgery Branch; National Cancer Institute; National Institutes of Health ; Bethesda, MD USA ; Department of Immunology; H Lee Moffitt Cancer Center ; Tampa, FL USA.
9
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.

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 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.

KEYWORDS:

B- and T-lymphocyte attenuator; CD8+ effector-memory; T cell survival/persistence; melanoma; tumor-infiltrating lymphocytes

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