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Review
. 2017 Sep 22:8:1178.
doi: 10.3389/fimmu.2017.01178. eCollection 2017.

Natural Killer T Cells in Cancer Immunotherapy

Shiny Nair  1 , Madhav V Dhodapkar  1
Affiliations
Review

Natural Killer T Cells in Cancer Immunotherapy

Shiny Nair et al. Front Immunol. .

Abstract

Natural killer T (NKT) cells are specialized CD1d-restricted T cells that recognize lipid antigens. Following stimulation, NKT cells lead to downstream activation of both innate and adaptive immune cells in the tumor microenvironment. This has impelled the development of NKT cell-targeted immunotherapies for treating cancer. In this review, we provide a brief overview of the stimulatory and regulatory functions of NKT cells in tumor immunity as well as highlight preclinical and clinical studies based on NKT cells. Finally, we discuss future perspectives to better harness the potential of NKT cells for cancer therapy.

Keywords: CD1d; dendritic cells; glycolipid antigens; innate immunity; natural killer T.

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Figures

Figure 1
Figure 1
Interactions and cross talk between different subsets of natural killer T (NKT) cells and other immune cells in tumor microenvironment (TME). Antigenic activated type I NKT cells can promote antitumor immunity by directly killing tumor cells in a CD1d-dependent and -independent mechanism. Type I NKT cells can recognize self or foreign lipid antigens presented by different CD1d-expressing antigen-presenting cells (APCs) in TME such as dendritic cells (DCs), TAMs, B cells, and neutrophils. On activation type I NKT cells can produce various Th1 and Th2 cytokines leading to reciprocal activation and or modulation of the APCs as well as other effector lymphocytes. Major type I NKT cytokine that helps activate DCs and CD8+ T cells is interferon-γ (IFN-γ). Type I NKT cells and DCs reciprocally activate each other via CD1d-TCR/lipid antigen and CD40–CD40L interactions. IL-12 produced by type I NKT cell matured DCs stimulates natural killer (NK), NKT, and MHC-restricted T cells to produce more IFN-γ which can secondarily activate other antitumor-promoting effector lymphocytes. Mature DCs derived factors as well as costimulatory receptors can activate CD8+ T cells to promote adaptive immunity. Type I NKT cells enhance tumor immunity by subduing the actions of tumor supporting cells such as TAMs, MDSCs, and suppressive neutrophils. In some instances, type II NKT cells have been shown to suppress the activation of type I NKT cells, T cells, NK cells and enhance development of tumor-associated MDSCs, aiding in tumor growth. iTCR, invariant TCR; IL-12, interleukin 12; IL-12R, IL-12 receptor; CXCL16, chemokine ligand 16; CXCR6, chemokine receptor 6; MDSCs, myeloid-derived suppressor cell; TAM, tumor-associated macrophages; ARG1, arginase 1; NOS, nitrous oxide synthase; SAA-1, serum amyloid A1; TCR, T cell receptor.
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