CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: α-Galactosylceramide and Beyond.

Lisa A King,Hans J Van Der Vliet,Roeland Lameris,Tanja D De Gruijl

doi:10.3389/fimmu.2018.01519

Lisa A King, Hans J Van Der Vliet + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2018.01519

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Abstract

CD1d-restricted invariant natural killer T (iNKT) cells are considered an attractive target for cancer immunotherapy. Upon their activation by glycolipid antigen and/or cytokines, iNKT cells can induce direct lysis of tumor cells but can also induce an antitumor immune response via their rapid production of proinflammatory cytokines that trigger the cytotoxic machinery of other components of the innate and adaptive immune system. Here, we provide an overview of various therapeutic approaches that have been evaluated or that are currently being developed and/or explored. These include administration of α-GalCer or alternative (glyco) lipid antigens, glycolipid-loaded antigen-presenting cells and liposomes, strategies that enhance CD1d expression levels or are based on ligation of CD1d, adoptive transfer of iNKT cells or chimeric antigen receptor iNKT cells, and tumor targeting of iNKT cells.

Highlights

Reviewed by: François Trottein, Centre national de la recherche scientifique (CNRS), France Toshinori Nakayama, Chiba University, Japan
CD1d-restricted invariant natural killer T cells are considered an attractive target for cancer immunotherapy
Two CD1d-restricted NKT cell subtypes exist, the classical invariant natural killer T (iNKT) and non-classical NKT subsets expressing a diverse T cell receptor (TCR) repertoire [1]. Both subsets are able to secrete immunoregulatory cytokines upon glycolipid recognition presented via the human leukocyte antigen class I-related molecule CD1d [2]. iNKT cells release, upon their interaction with CD1d, a broad spectrum of cytokines, which in turn activate T cells, natural killer (NK) cells, B cells, and dendritic cells (DCs), thereby initiating a T helper (Th) 1, Th2 or Th17 response [1, 3,4,5,6]

Summary

IN NANOVECTORS

Another approach that is being explored with the aim to enhance the effect of α-GalCer entails its incorporation into nanovectors, which can act as vaccine carriers to induce an immune response by delivering their content to endosomes. Khan et al used liposomes incorporating glycosphingolipids isolated from Spingomonas paucimobilis, which can, like α-GalCer, activate iNKT cells [38] When these liposomes were loaded ex vivo onto bone marrow-derived DCs and used as treatment for mice with dimethyl-α-benzanthracene-induced tumors, a more sustained secretion of IFN-γ and a potent antitumor response was induced compared to administration of glycosphingolipids alone. Delivery of α-GalCer to CD8α+ DCs via this route enhanced iNKT cell transactivation of NK and T cells and a cytotoxic T cell response in in vivo mouse models and could promote both prophylactic and therapeutic antitumor responses in an advanced solid tumor model in mice This approach could target human CLEC9A-expressing DC to mediate the expansion of tumor self-antigen specific CD8+ T cells in PBMCs samples of melanoma patients in vitro, thereby underscoring the translational potential of this approach. All-trans retinoic acid and certain chemotherapeutics have been reported to increase CD1d expression levels and are, of potential interest either alone or in combination with other iNKT cell-based therapeutic approaches [36, 42]

ADOPTIVE TRANSFER OF iNKT CELLS

TUMOR TARGETING OF iNKT CELLS

CONCLUDING REMARKS