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Int. J. Mol. Sci. 2018, 19(3), 752; doi:10.3390/ijms19030752

Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma

Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
Transplantation Immunobiology Section, School of Biological Sciences and Biotechnology, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital, 24071 Leon, Spain
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, IME, 60590 Frankfurt, Germany
These authors contributed equally to this paper.
Author to whom correspondence should be addressed.
Received: 6 February 2018 / Revised: 2 March 2018 / Accepted: 5 March 2018 / Published: 7 March 2018
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Natural Killer T cells (NKT cells) are emerging as critical regulators of pro- and anti-tumor immunity, both at baseline and in therapeutic settings. While type I NKT cells can promote anti-tumor immunity, their activity in the tumor microenvironment may be limited by negative regulators such as inhibitory immune checkpoints. We observed dominant expression of B- and T-lymphocyte attenuator (BTLA) on type I NKT cells in polyoma middle T oncogene-driven (PyMT) murine autochthonous mammary tumors. Other immune checkpoint receptors, such as programmed cell death 1 (PD-1) were equally distributed among T cell populations. Interference with BTLA using neutralizing antibodies limited tumor growth and pulmonary metastasis in the PyMT model in a therapeutic setting, correlating with an increase in type I NKT cells and expression of cytotoxic marker genes. While therapeutic application of an anti-PD-1 antibody increased the number of CD8+ cytotoxic T cells and elevated IL-12 expression, tumor control was not established. Expression of ZBTB16, the lineage-determining transcription factor of type I NKT cells, was correlated with a favorable patient prognosis in the METABRIC dataset, and BTLA levels were instrumental to further distinguish prognosis in patents with high ZBTB16 expression. Taken together, these data support a role of BTLA on type I NKT cells in limiting anti-tumor immunity. View Full-Text
Keywords: natural killer T cells; inflammation; cancer natural killer T cells; inflammation; cancer

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Sekar, D.; Govene, L.; del Río, M.-L.; Sirait-Fischer, E.; Fink, A.F.; Brüne, B.; Rodriguez-Barbosa, J.I.; Weigert, A. Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma. Int. J. Mol. Sci. 2018, 19, 752.

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