Preface: NKT Cells for Tumor Immunotherapy

Abstract

Natural killer (NK) T cells are unconventional T cells restricted by an MHC class I-like molecule, CD1d, which presents lipid antigens. There are two types of NKT cells defined by the TCR that they express. Type I or invariant NKT (iNKT) cells express a semi-invariant TCRα chain consisting of Vα14 and Jα18 gene segments and a diverse TCRβ chain. Type II NKT cells express variant TCR α and β chains. 1,2 iNKT cells have three major functional subsets, NKT1, NKT2, and NKT17, similar to CD4 + T cell subsets, Th1, Th2, and Th17. iNKT cells have been demonstrated to facilitate tumor immunity in many pre-clinical studies since their prototypic glycolipid antigen, α-galactosylceramide (α-GalCer), was discovered as iNKT cell agonistic antigen. Upon the recognition of α-GalCer, iNKT cells strongly become activated, rapidly produce a large amount of various cytokines and modulate multiple types of immune cells. The interaction with α-GalCer enables the DCs to mature and become activated to facilitate antigen presentation to T cells and IL-12 production. DCs activation also facilitates antigen cross-presentation to CD8 + T cells. The induction of IL-12 and IFN-γ activates NK cell-and CD8 + T cell-mediated tumor immunity. α-GalCer-activated iNKT cells also modulate or reprogram myeloid cells such as macrophages and neutrophils to express immunostimulatory functions. iNKT cells also interact with B cells to function like Tfh cells. Although α-GalCer inoculation in vivo induces massive activation of iNKT cells, it has certain limitations to induce effective tumor immunity. In vivo administration of free α-GalCer induces long-term functional anergy or immune deviation that limits the number of doses that could be administered in vivo. A single-agent inoculation of α-GalCer shows no or very limited therapeutic efficacy while it induces strong anti-tumor immune responses when administered simultaneously with tumor implantation. One potential solution for the anergy induction at least in part is to deliver α-GalCer to professional antigen-presenting cells (APCs), which can provide critical co-stimulatory signals to iNKT cells. As APC-iNKT interaction activates antigen-presenting