α-Galactosylceramide but Not Phenyl-Glycolipids Induced NKT Cell Anergy and IL-33–Mediated Myeloid-Derived Suppressor Cell Accumulation via Upregulation of egr2/3

Abstract

Strategies for cancer immunotherapy include activating immune system for therapeutic benefit or blockade of immune checkpoints. To harness innate immunity to fight cancer, a-galactosylceramide (a-GalCer) has been used to activate NKT cells. Unfortunately, administration of a-GalCer causes long-term NKT cell anergy, but the molecular mechanism is unclear. In this study, we showed that a-GalCer-triggered egr2/3, which induced programmed death 1 and cbl-b in NKT cells, leading to NKT cell anergy. We also uncovered the induction of the immunosuppressive myeloid-derived suppressor cells (MDSCs) in the spleen by a-GalCer that might attenuate its antitumor efficacy. The accumulation of MDSC was accompanied by 20-fold rise in their arg-1 mRNAs and enhanced expression of programmed death 1/programmed death ligand 1. Furthermore, a-GalCer-induced egr-2/3 in hepatic NKT cells upregulated their TRAIL in addition to Fas ligand (FasL) and induced alarm signaling molecule IL-33 in Kupffer cells, presumably because of liver damage triggered by TRAIL/FasL. We further demonstrated that IL-33-stimulated macrophages produce G-CSF, which in turn, boosted MDSCs. Thus, a-GalCer-induced FasL/TRAIL and IL-33 provided a novel mechanism underlying a-GalCer-induced hepatotoxicity and MDSC accumulation. In contrast, analogs of a-GalCer containing phenyl group in the lipid tail could neither induce NKT anergy nor enhance MDSCs accumulation. Furthermore, tumor-infiltrating MDSCs in mice injected repeatedly with a-GalCer were 2-fold higher than those treated with phenyl-glycolipids. These results not only revealed the induction of MDSC via IL-33 as a new mechanism for a-GalCer-elicited immunosuppression but also provided one of the mechanisms underlying the superior antitumor potency of phenyl-glycolipids. Our findings have important implications for the development of NKT-stimulatory glycolipids as vaccine adjuvants and anticancer therapeutics.

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

“…NKT cell activation in a mouse model of multiple sclerosis was reported to provide protection via the induction of MDSCs, 44 and administration of free a-GalCer has been shown to increase MDSCs in a hepatotoxicity model. 37 In contrast, NKT cells suppresses MDSC accumulation during viral infection, 29 and activated NKT cells can induce MDSC differentiation into DCs. 29,46,57,58 In expanded memory T cell cultures, an increased number of mouse CD49b C T cells or human CD161 C T cells reduced the suppressive effects of MDSCs, leading to enhanced IFNg production in response to tumor antigens.…”

“…As repeated NKT cell stimulation with free glycolipid is known to induce anergy, [36][37][38] we performed a dose response study using single injections of a-GalCer. A significant increase in overall survival time was observed with the highest dose (i.p.…”

“…24,42,43 However, the relationship between NKT cells and MDSCs is unclear as NKT cells have been shown to suppress or promote MDSC accumulation and activity in different settings. 29,37,[44][45][46] We prepared hematoxylin and eosin-stained cytospins of peripheral blood samples to characterize the leukocyte populations. Compared to na€ ıve controls, tumor bearing mice had significantly higher numbers of granulocytic cells with few lymphocytes and monocytes (Fig.…”

Selective Conditions Are Required for the Induction of Invariant NKT Cell Hyporesponsiveness by Antigenic Stimulation

“…2A, B and 3A, B ). It has been suggested that the ability of an Ag to induce i NKT cell hypo-responsiveness correlates with its antigenic strength (23, 38). However, our data do not support this model.…”

Biomarkers for glioma immunotherapy: the next generation

“…Meanwhile, the list of single factors with direct and indirect influence on the evolution of the immune response continues to grow—particularly small molecule metabolites and the pathways regulating them (e.g. indoleamine dioxygenase [74], arginase [75], and α-galactosylceramide [76]), “danger” pathways (e.g., DAMPs, TLRs, and high-mobility group box-1 release [77], for a review see [78]), and innate immune, wound-healing, and inflammatory signals (e.g. STING pathway ligands, inflammasome expression, TGF-β family signaling, and NFκB induction).…”