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

Int J Mol Sci. 2018 Mar 7;19(3):752. 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.

Keywords: cancer; inflammation; natural killer T cells.

MeSH terms

  • Animals
  • Biomarkers
  • Biomarkers, Tumor
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Immunophenotyping
  • Lymphocyte Count
  • Mice
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism*
  • 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
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • BTLA protein, mouse
  • Biomarkers
  • Biomarkers, Tumor
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Promyelocytic Leukemia Zinc Finger Protein
  • Receptors, Immunologic
  • Zbtb16 protein, mouse