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Open AccessArticle

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

1
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
2
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
3
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, IME, 60590 Frankfurt, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Int. J. Mol. Sci. 2018, 19(3), 752; https://doi.org/10.3390/ijms19030752
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)
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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