Original Article

Cancer Immunology, Immunotherapy

, Volume 60, Issue 4, pp 547-558

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

  • Kevin DurganAffiliated withResearch Division, Puget Sound Blood Center
  • , Mohamed AliAffiliated withResearch Division, Puget Sound Blood Center
  • , Paul WarnerAffiliated withResearch Division, Puget Sound Blood Center
  • , Yvette E. LatchmanAffiliated withResearch Division, Puget Sound Blood CenterDepartment of Medicine, Division of Hematology, University of Washington Email author 

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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