Invariant NKT cells as novel targets for immunotherapy in solid tumors

Abstract

Natural killer T (NKT) cells are a small population of lymphocytes that possess characteristics of both innate and adaptive immune cells. They are uniquely poised to respond rapidly to infection and inflammation and produce cytokines that critically shape the ensuing adaptive cellular response. Therefore, they represent promising therapeutic targets. In cancer, NKT cells are attributed a role in immunosurveillance. NKT cells also act as potent activators of antitumor immunity when stimulated with a synthetic agonist in experimental models. However, in some settings, NKT cells seem to act as suppressors and regulators of antitumor immunity. Here we briefly review current data supporting these paradoxical roles of NKT cells and their regulation. Increased understanding of the signals that determine the function of NKT cells in cancer will be essential to improve current strategies for NKT-cell-based immunotherapeutic approaches.

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 γδ 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.

Figure 2

Multiple opportunities exist for innovations in iNKT-based cancer immunotherapy. Development of synthetic glycolipids that promote Th1 cytokine production by iNKT cells and the use of these agonists, including α-GalCer, as powerful adjuvants in cancer vaccines. Combinatorial approaches of iNKT stimulation with standard chemo-/radiotherapy or novel therapies that target other immune cells may result in synergistic effects. Blocking the activation of regulatory iNKT cells will be beneficial in tumors where regulatory iNKT cells play a key suppressor role. Optimization of protocols for ex vivo loading and maturation of autologous DCs will ensure consistent and reliable stimulation of iNKT cells in vivo. CD1d-expressing tumor cells can also be used as source of iNKT-stimulating APCs.