Invariant NKT Cells as Novel Targets for Immunotherapy in Solid Tumors

Figure 1

In cancer, iNKT cells play a dual role that can promote (left) or suppress (right) the antitumor immune response. In the presence of a strong activator (α-GalCer), iNKT cells promote the ability of DCs to prime effector cells through IL-12 production and upregulation of costimulatory molecules. Ligation of CD40L on the surface of DCs provides positive feedback enhancing iNKT cell activation. These events ultimately lead to downstream activation of antitumor effectors such as NK cells, CD8+, and CD4+ T-cells. Other iNKT agonists (β-ManCer) stimulate TNF-α production, leading to activation of antitumor γ δ T-cells. iNKT cells may also promote antitumor immunity by directly killing protumorigenic macrophages (TAMs). On the other hand, IL-13 production by iNKT cells can trigger TGF-β production by suppressive MDSCs. TGF-β directly inhibits effector CD8+ activity and can induce FoxP3 expression in iNKT cells. iNKT cells can also induce DCs to acquire a tolerogenic phenotype, including expression of DC-LAMP, PD-L, and CD33. Data suggest that type II NKT cells perform always immunosuppressive functions in cancer.