Harnessing the Power of Invariant Natural Killer T Cells in Cancer Immunotherapy

Abstract

Invariant natural killer T (iNKT) cells are a distinct subset of innate-like lymphocytes bearing an invariant T-cell receptor, through which they recognize lipid antigens presented by monomorphic CD1d molecules. Upon activation, iNKT cells are capable of not only having a direct effector function but also transactivating NK cells, maturing dendritic cells, and activating B cells, through secretion of several cytokines and cognate TCR-CD1d interaction. Endowed with the ability to orchestrate an all-encompassing immune response, iNKT cells are critical in shaping immune responses against pathogens and cancer cells. In this review, we examine the critical role of iNKT cells in antitumor responses from two perspectives: (i) how iNKT cells potentiate antitumor immunity and (ii) how CD1d⁺ tumor cells may modulate their own expression of CD1d molecules. We further explore hypotheses to explain iNKT cell activation in the context of cancer and how the antitumor effects of iNKT cells can be exploited in different forms of cancer immunotherapy, including their role in the development of cancer vaccines.

Keywords: CD1d molecules; innate immune response; invariant natural killer T cells; lipid antigens; tumor immunology.

Figure 1

Mechanisms of tumor evasion from invariant natural killer T (iNKT) immunosurveillance. Some tumors cells escape detection by iNKT cells via the regulation of surface CD1d, by: (1) heterochromatin formation at the CD1d locus by histone deacetylases (71, 72); or (2) improper folding and retention of CD1d in the ER (69). Other mechanisms to escape iNKT cell detection include: (3) engagement of surface CD1d with the inhibitory NK receptor Ly49, leading to the induction of iNKT cell anergy (70); (4) inhibitory signaling through PD1/PDL1 between iNKT cells and tumor cells (139); and (5) CD1d-dependent suppression of iNKT cells through presentation of the inhibitory, tumor-derived glycolipid GD3. GD3 production is also driven by the secretion of tumor-derived VEGF (75).

Figure 2

Potential mechanisms of invariant natural killer T (iNKT) cell activation in cancer. Tumor cells subject to drugs or conditions that induce stress might activate iNKT cells through several pathways: (1) secretion or passive release of DAMPs, such as HMGB1, that bind RAGE receptors directly on iNKT cells or TLR4/RAGE receptors on CD1d+ antigen-presenting cells (APCs), leading to the presentation of an immunogenic self-lipid antigen (46, 88, 90); (2) paracrine (from APCs) or autocrine release of ATP into the extracellular environment for uptake by iNKT cells, ultimately leading to iNKT cell activation (94, 95); (3) binding of the surface DAMP calreticulin to TRAIL on iNKT cells (–110); (4) induction of ER stress in CD1d+ cells, due to the suboptimal physiological tumor microenvironment, might trigger the alternate loading immunogenic self-lipid antigen(s), resulting in enhanced iNKT cell activation (–113).