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

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 inh...

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Autores principales: Sekar, Divya, Govene, Luisa, del Río, María-Luisa, Sirait-Fischer, Evelyn, Fink, Annika F., Brüne, Bernhard, Rodriguez-Barbosa, José I., Weigert, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877613/
https://www.ncbi.nlm.nih.gov/pubmed/29518903
http://dx.doi.org/10.3390/ijms19030752
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author Sekar, Divya
Govene, Luisa
del Río, María-Luisa
Sirait-Fischer, Evelyn
Fink, Annika F.
Brüne, Bernhard
Rodriguez-Barbosa, José I.
Weigert, Andreas
author_facet Sekar, Divya
Govene, Luisa
del Río, María-Luisa
Sirait-Fischer, Evelyn
Fink, Annika F.
Brüne, Bernhard
Rodriguez-Barbosa, José I.
Weigert, Andreas
author_sort Sekar, Divya
collection PubMed
description 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.
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spelling pubmed-58776132018-04-09 Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma Sekar, Divya Govene, Luisa del Río, María-Luisa Sirait-Fischer, Evelyn Fink, Annika F. Brüne, Bernhard Rodriguez-Barbosa, José I. Weigert, Andreas Int J Mol Sci Article 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. MDPI 2018-03-07 /pmc/articles/PMC5877613/ /pubmed/29518903 http://dx.doi.org/10.3390/ijms19030752 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sekar, Divya
Govene, Luisa
del Río, María-Luisa
Sirait-Fischer, Evelyn
Fink, Annika F.
Brüne, Bernhard
Rodriguez-Barbosa, José I.
Weigert, Andreas
Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma
title Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma
title_full Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma
title_fullStr Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma
title_full_unstemmed Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma
title_short Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma
title_sort downregulation of btla on nkt cells promotes tumor immune control in a mouse model of mammary carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877613/
https://www.ncbi.nlm.nih.gov/pubmed/29518903
http://dx.doi.org/10.3390/ijms19030752
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