Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy

Abstract

iNKT cells are a subset of innate-like T cells that utilize an invariant TCR alpha chain complexed with a limited repertoire of TCR beta chains to recognize specific lipid antigens presented by CD1d molecules. Because iNKT cells have an invariant TCR, they can be easily identified and targeted in both humans and mice via standard reagents, making this a population of T cells that has been well characterized. iNKT cells are some of the first cells to respond during an infection. By making different types of cytokines in response to different infection stimuli, iNKT cells help determine what kind of immune response then develops. It has been shown that iNKT cells are some of the first cells to respond during infection with a pathogen and the type of cytokines that iNKT cells make help determine the type of immune response that develops in various situations. Indeed, along with immunity to pathogens, pre-clinical mouse studies have clearly demonstrated that iNKT cells play a critical role in tumor immunosurveillance. They can mediate anti-tumor immunity by direct recognition of tumor cells that express CD1d, and/or via targeting CD1d found on cells within the tumor microenvironment. Multiple groups are now working on manipulating iNKT cells for clinical benefit within the context of cancer and have demonstrated that targeting iNKT cells can have a therapeutic benefit in patients. In this review, we briefly introduce iNKT cells, then discuss preclinical data on roles of iNKT cells and clinical trials that have targeted iNKT cells in cancer patients. We finally discuss how future trials could be modified to further increase the efficacy of iNKT cell therapies, in particular CAR-iNKT and rTCR-iNKT cells.

Keywords: CD1d; NKT cells; cancer immunotherapy; iNKT cells; monoclonal antibody.

Figure 1

Invariant NKT (iNKT) cell contribution to initiating immune reactions via a positive feedback loop with dendritic cells (DCs). The contribution of iNKT cells to immune surveillance is linked to DC maturation. DCs produce IL-12 and present lipid antigens on CD1d (an MHC class 1 homolog) to stimulate iNKT cell production of IFNγ. The relative contribution of IL-12 or lipid-CD1d to iNKT cell activation is variable and context dependent. Activated iNKT cells produce IFNγ and co-stimulate DCs via CD40L-CD40 interactions to promote DCs to produce IL-12. This IL-12 then further activates iNKT cells in a positive feedback loop. Following activation of iNKT cells, iNKT cell-produced IFNγ and other iNKT-DC interactions (e.g., CD40L-CD40) mature DCs and promote production of IL-12, which further activates iNKT cells in a positive feedback loop.

Figure 2

Invariant NKT (iNKT) cell activity within the tumor microenvironment (TME). iNKT cells can function within the TME via direct or indirect interactions with tumor cells. (A) In the direct activation pathway, iNKT cells recognize lipid-CD1d complexes on the surface of tumor cells and then directly mediate killing of tumor cells. By making inflammatory cytokines like IFNγ, this also helps TME-resident NK cells perform their anti-tumor cell effector functions (24, 35, 36, 43, 44). (B) In the indirect activation pathway, iNKT cells recognize lipid-CD1d complexes on the surface of TME-resident antigen presenting cells (APCs) or tissue-associated macrophages (TAMs) (29). This interaction leads to iNKT cell-mediated killing of immunosuppressive TAMs, leading to a less immunosuppressive environment where tumor-infiltrating NK cells can better perform their functions. Alternately, if the CD1d is on the surface of a TME-resident APC, the iNKT cell can activate that APC and stimulate production of IL-12, helping resident effector cells like NK cells overcome the immunosuppressive state of the tumor (32).

Figure 3

Invariant NKT (iNKT) cells are a viable cell vector for emerging CAR and rTCR therapies. Unlike bulk T cell preparations that are currently used for chimeric antigen receptor (CAR) or recombinant TCR (rTCR) T cell therapies, the endogenous iNKT-TCR has anti-tumor function (left side). In contrast, the bulk T cell endogenous TCRs do not contribute to the anti-tumor function of the cell (middle picture). Instead, the bulk T cell endogenous TCR is a liability, endowing the cells with the potential for graft versus host disease (GvHD) or other off-target effects. While GvHD is a common concern for both CAR-T and rTCR-T allogeneic therapy and at least a possibility due to mispairing for autologous rTCR-iNKT, iNKT cells are shown in pre-clinical models to suppress, not cause GvHD during allogeneic transfer, making for a safer therapeutic approach. Additionally, iNKT cells expressing a CAR or rTCR (right picture) would be endowed with two different anti-tumor receptors. This would allow iNKT cells to target the tumor directly with the CAR or rTCR while its endogenous iNKT-TCR would be able to target the tumor microenvironment and/or the tumor itself, depending on if the tumor expressed CD1d. Either way, CAR-iNKT and rTCR-iNKT therapies would have an endogenous TCR that contributes to tumor clearance instead of be a hindrance.