Cancer Immunology, Immunotherapy

, Volume 60, Issue 4, pp 547–558 | Cite as

Targeting NKT cells and PD-L1 pathway results in augmented anti-tumor responses in a melanoma model

  • Kevin Durgan
  • Mohamed Ali
  • Paul Warner
  • Yvette E. Latchman
Original Article

Abstract

Invariant or Type 1 NKT cells (iNKT cells) are a unique population of lymphocytes that share characteristics of T cells and natural killer (NK) cells. Various studies have shown that positive costimulatory pathways such as the CD28 and CD40 pathways can influence the expansion and cytokine production by iNKT cells. However, little is understood about the regulation of iNKT cells by negative costimulatory pathways. Here, we show that in vivo activation with α-GalCer results in increased cytokine production and expansion of iNKT cells in the absence of programmed cell death ligand-1 (PD-L1, B7-H1, and CD274). To study whether PD-L1 deficiency on NKT cells would enhance antigen-specific T-cell responses, we utilized CD8+ OT-1 OVA transgenic T cells. α-GalCer enhanced the expansion and cytokine production of OT-1 CD8+ cells after adoptive transfer into wild-type recipients. However, this expansion was significantly enhanced when OT-1 CD8+ T cells were adoptively transferred into PD-L1−/− recipients. To extend these results to a tumor model, we used the B16 melanoma system. PD-L1−/− mice given dendritic cells loaded with antigen and α-GalCer had a significant reduction in tumor growth and this was associated with increased trafficking of antigen-presenting cells and CD8+ T cells to the tumors. These data demonstrate that abrogating PDL1:PD-1 interactions during the activation of iNKT cells amplifies an anti-tumor response when coupled with DC vaccination.

Keywords

Costimulation Programmed cell death-1 Programmed cell death ligand-1 Tumor Invariant NKT cells T cells 

Supplementary material

262_2010_963_MOESM1_ESM.pdf (1.2 mb)
Supplementary material 1 (PDF 1.16 MB)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Kevin Durgan
    • 1
  • Mohamed Ali
    • 1
  • Paul Warner
    • 1
  • Yvette E. Latchman
    • 1
    • 2
  1. 1.Research DivisionPuget Sound Blood CenterSeattleUSA
  2. 2.Department of Medicine, Division of HematologyUniversity of WashingtonSeattleUSA

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