The Current Landscape of NKT Cell Immunotherapy and the Hills Ahead

Abstract

NKT cells are a specialized subset of lipid-reactive T lymphocytes that play direct and indirect roles in immunosurveillance and anti-tumor immunity. Preclinical studies have shown that NKT cell activation via delivery of exogenous glycolipids elicits a significant anti-tumor immune response. Furthermore, infiltration of NKT cells is associated with a good prognosis in several cancers. In this review, we aim to summarize the role of NKT cells in cancer as well as the current strategies and status of NKT cell immunotherapy. This review also examines challenges and future directions for improving the therapy.

Keywords: CAR-NKT cells; adoptive transfers; cancer; cancer vaccines; checkpoint inhibitors; iNKT cells; immunotherapy; natural killer T cells; type II NKT cells; α-galactosylceramide.

Figure 1

The complex network between iNKT cells and other immune cells in the tumor microenvironment. (A) iNKT cells activated by antigenic, or cytokine stimulation can promote anti-tumor immunity by directly eliminating tumor cells through various cell-to-cell interactions (e.g., invariant TCR → antigen-loaded CD1d, NKG2D → ligand) that induce the release of cytotoxic granules (e.g., granzyme B, perforin) or apoptotic signaling (e.g., FasL → Fas). (B) iNKT cells and other effector lymphocytes may be recruited to the TME via chemokines (e.g., CXCL9, CXCL10, CXCL11, CXCL16) released via immunogenic cell death from tumor cell lysis, or from other tumor-infiltrating immune cells. iNKT cells activated by antigen-presenting cells (APCs) such as dendritic cells (DCs) or B cells can indirectly promote anti-tumor immunity. Upon cognate TCR-CD1d interactions, iNKT cells upregulate CD40L that induces APC maturation and release cytokines that mediate activation of other effector lymphocytes (NK cells and CD8 T cells). (C) iNKT cells may also induce long-lasting anti-tumor immunity by promoting the formation of effector memory CD4 and CD8 T cells that are tumor specific. iNKT cell-mediated activation of DCs or B cells promotes the presentation of tumor antigens to CD4 and CD8 T cells. iNKT cell-derived cytokines also promote expansion and differentiation of effector and memory T cells, further promoting persistent anti-tumor immunity. (D) iNKT cells also interact with suppressor cells in the TME, including T regulatory (Treg) cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and type II NKT cells. Tregs and type II NKT cells cooperate to cross-regulate iNKT cells in the tumor and inhibit their anti-tumor functions. Tregs, MDSCs, and TAMs can produce IL-10 to promote tolerance and inhibit the effector functions of neighboring CD4 T, CD8 T, and NK cells. MDSCs and TAMs may also inhibit effector lymphocytes via the production of TGF-β and PGE₂, whereas PGE₂ induces Tregs. Type II NKT cells may recruit and activate MDSCs via IL-13, which consequently enhances their TGF-ß production. MDSCs may recruit Tregs into the TME via chemokines such as CCL5, CCL20, or CCL22. iNKT cells oppose the suppressive functions of MDSCs and TAMs by polarizing macrophages towards a favorable M1 phenotype, inhibiting MDSC suppressive functions, or by lysing MDSCs/TAMs.

Figure 2

CAR-NKT cells versus CAR-T cells; how do they measure up? CAR-NKT cells have several advantages over their CAR-T cell counterparts. For example, CAR-T cells can induce graft versus host disease (GvHD), cytokine release storms (CRS), neurotoxicity, and on-target off-tumor side effects in the recipient. This is often due to a limited repertoire of antigen recognition receptors (e.g., TCR, CAR receptors) and higher secretion of cytokines such as IL-6 causing CRS. CAR-NKT cells instead display a much-improved safety profile with minimal side effects due to their distinct cytokine profile (failing to induce CRS) and a broad spectrum of antigen recognition receptors in addition to their CAR receptor. CAR-T cells are also challenged with the inability to counteract the suppressive nature of the tumor microenvironment, and often succumb to exhaustion or anergy. CAR-NKT cells can overcome immunosuppression by targeting and inhibiting myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) via cytotoxic effects or macrophage polarization, respectively. CAR-NKT cells may also be stimulated via glycolipids such as α-GalCer and can infiltrate the solid tumor, unlike CAR-T cells which frequently exhibit impaired trafficking to the tumor site.