Invariant natural killer T (iNKT) cells are a subset of CD1d (antigen presenting cell−ligand)-dependent NKT cells that express an invariant T-cell receptor alpha chain. iNKT-induced NK cell activation leads to maturation of dendritic cells. Ideally, cancer immunotherapy would be more effective when involving both innate and adaptive immune functions. Since mature dendritic cells link the two immune mechanisms, strategies targeting dendritic cells matured by iNKT cells (iNKT-licensed dendritic cells) have been studied.
Role of NK Cells in iNKT Function and Therapy
iNKT cells are crucial for antitumor immune responses. For example, chemically-induced sarcoma tumor induction in iNKT-deficient mice was prevented upon transfer of iNKT cells into the mice. When NKT cells are activated, dendritic cells express ligands that bind to NK cells, thus activating the NK cells. Dendritic cells also release IL-12, which binds to IL-12 receptors on NK cells, leading to the release of cytokines from the NK cells.
In addition to dendritic cells, NK cells themselves can have adjuvant effects. The cytokines they produce (such as IFN-gamma and TNF-alpha) promote maturation of dendritic cells leading to stimulation of cytotoxic T cells. Further, the magnitude of the adaptive response depends on the nature of the initiating innate immunity including iNKT level, the type of target cell ligands, dendritic cell properties, and expression level of CD1d (modulates iNKT cell activation).
Linking Innate and Adaptive Therapy as an Antitumor Strategy
Tumor antigen and NKT cell ligands must be delivered simultaneously to dendritic cells in vivo. If the dendritic cells are already mature when exposed to antigen, they will be unable to phagocytize the antigen. Adding tumor antigen hours after NKT cell ligand does not elicit a T cell response. Therefore, a strategy that uses a cell type that expresses tumor antigen and CD1d loaded with NKT cell ligand (adjuvant vector cells) may have utility for hematological neoplasias and solid tumors.
Another approach uses a bacterial vaccine expressing tumor antigen and NKT ligand, and this can elicit cytotoxic T cell activation. Patients with cancer with decreased iNKT cell levels may benefit from a technology that involves reprogramming subfunctional iNKT cells to re-differentiate into functional iNKT cells. Taken together, iNKT-induced dendritic cell immunotherapy may represent an effective approach to antitumor cell therapy.
Fujii, S., & Shimizu, K. (2017). Exploiting Antitumor Immunotherapeutic Novel Strategies by Deciphering the Cross Talk between Invariant NKT Cells and Dendritic Cells. Frontiers In Immunology, 8. doi:10.3389/fimmu.2017.00886