Expression of leukotriene B₄ receptor-1 on CD8⁺ T cells is required for their migration into tumors to elicit effective antitumor immunity

J Immunol. 2013 Sep 15;191(6):3462-70. doi: 10.4049/jimmunol.1300967. Epub 2013 Aug 19.

Abstract

Leukotriene B₄ (LTB₄) receptor (BLT)1 is expressed on variety of immune cells and has been implicated as a mediator of diverse inflammatory diseases. However, whether biological responses initiated via this receptor generate tumor-promoting inflammation or antitumor immunity remains unexplored. In this study, we investigated the role of BLT1 in antitumor immunity using syngeneic TC-1 cervical cancer model, and observed accelerated tumor growth and reduced survival in BLT1⁻/⁻ mice compared with BLT1⁺/⁺ mice. Analysis of the tumor infiltrates by flow cytometry and confocal microscopy revealed a significant decrease in effector immune cells, most notably, CD8⁺ T cells and NK cells in the tumors of the BLT1⁻/⁻ mice. Gene expression profiling confirmed the dramatic decrease of IFN-γ, granzyme B, and IL-2 in tumors growing in BLT1⁻/⁻ mice. Furthermore, depletion of CD8⁺ T cells enhanced the tumor growth in BLT1⁺/⁺ but not in BLT1⁻/⁻ mice. However, similar levels of Ag-dependent CD8⁺ T cell-mediated killing activity were observed in spleens of BLT1⁺/⁺ and BLT1⁻/⁻ mice. Adoptive transfer of CD8⁺ T cells from tumor-bearing BLT1⁺/⁺ but not BLT1⁻/⁻ mice significantly reduced tumor growth and increased the survival of Rag2⁻/⁻ mice. Although the homeostatic proliferation and expression profiles of other chemokine receptors of adoptively transferred BLT1⁺/⁺ and BLT1⁻/⁻ CD8⁺ T cells appears to be similar, BLT1⁺/⁺ T lymphocytes entered the tumors in greater numbers. These results suggest that BLT1 expression on CD8⁺ T cells plays an important role in their trafficking to tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Chemotaxis, Leukocyte / immunology*
  • Disease Models, Animal
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Lymphocytes, Tumor-Infiltrating
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Real-Time Polymerase Chain Reaction
  • Receptors, Leukotriene B4 / biosynthesis*
  • Uterine Cervical Neoplasms / immunology*
  • Uterine Cervical Neoplasms / metabolism

Substances

  • Ltb4r1 protein, mouse
  • Receptors, Leukotriene B4