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

• Published in: International journal of molecular sciences 2018-03, Vol.19 (3), p.752
• Main Authors: Sekar, Divya, Govene, Luisa, Del Río, María-Luisa, Sirait-Fischer, Evelyn, Fink, Annika F, Brüne, Bernhard, Rodriguez-Barbosa, José I, Weigert, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers; Biomarkers, Tumor; Breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; BTLA protein; Carcinoma; CD8 antigen; Cell death; Cell Line, Tumor; Cytotoxicity; Data processing; Disease Models, Animal; Down-Regulation; Female; Gene expression; Gene Expression Regulation, Neoplastic; Immune checkpoint; Immunophenotyping; Interleukin 12; Lymphocyte Count; Lymphocytes; Lymphocytes B; Lymphocytes T; Mammary gland; Metastases; Mice; Natural killer cells; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; PD-1 protein; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Promyelocytic Leukemia Zinc Finger Protein - genetics; Promyelocytic Leukemia Zinc Finger Protein - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Regulators; T cell receptors; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19030752

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.