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

摘要

Leukotriene B4 (LTB4) receptor, BLT1 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 anti-tumor 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 to 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 antigen 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. While 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.