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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 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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Author:Divya Sekar, Luisa Govene, María-Luisa del Río, Evelyn Nicole Joy Sirait-FischerORCiDGND, Annika F. FinkGND, Bernhard BrüneORCiD, José I. Rodriguez-Barbosa, Andreas WeigertORCiDGND
URN:urn:nbn:de:hebis:30:3-457983
DOI:https://doi.org/10.3390/ijms19030752
ISSN:1422-0067
ISSN:1661-6596
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29518903
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/03/07
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/03/15
Tag:cancer; inflammation; natural killer T cells
Volume:19
Issue:3, Art. 752
Page Number:12
First Page:1
Last Page:12
Note:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
HeBIS-PPN:432321578
Institutes:Medizin / Medizin
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0