Structure-Based Discovery of Glycolipids for CD1d-Mediated NKT Cell Activation:  Tuning the Adjuvant versus Immunosuppression Activity

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Invariant natural killer T cell (NKT) cells (iNKT cells) produce both T-helper 1 (Th1) and T-helper 2 cytokines in response to α-Galactosylceramide (α-GalCer) stimulation and are thought to be the important effectors in the regulation of both innate and adaptive immunity involved in autoimmune disorders, microbial infections, and cancers. However, the anticancer effects of α-GalCer were limited in early clinical trial. In this study, several analogs of α-GalCer, containing phenyl groups in the lipid tails were found to stimulate murine and human iNKT cells to secrete Th1-skewed cytokines and exhibit greater anticancer efficacy in mice than α-GalCer. We explored the possibility of different Vβ usages of murine Vα14 iNKT or human Vα24 iNKT cells, accounting for differential cytokine responses. However, T-cell receptor Vβ analysis revealed no significant differences in Vβ usages by α-GalCer and these phenyl glycolipid analogs. On the other hand, these phenyl glycolipids showed greater binding avidity and stability for iNKT T-cell receptor when complexed with CD1d. These findings suggest that CD1d-phenyl glycolipid complexes may interact with the same population of iNKT cells but with higher avidity and stability to drive Th1 polarization. Thus, this study provides a key to the rational design of Th1 biased CD1d reactive glycolipids in the future.immune-modulating activity | structure | interaction | cancer immunotherapy

Section: Resultsmentioning

confidence: 99%

Avidity of CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and anticancer efficacy

Lin

Chang

et al. 2011

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“…By adding -OMe, -F, or -CF 2 to the terminal benzene ring of compounds, C10 (6-carbon length), C11 (8-carbon length), and C16 (11-carbon length), glycolipids were able to induce a higher level of IFN-γ, whereas the introduction of an additional benzene ring to the terminal benzene ring of these compounds, dramatically reduced the ability to induce IFN-γ secretion. Our previous docking model study had indicated that introduction of a terminal phenyl group in the α-GalCer analogues appears to promote additional hydrogen bonding between the benzene ring of fatty acyl chain and the aromatic residues that are present on the wall of A′ pocket in the CD1d hydrophobic groove (19). It is likely that an addition of a small radical group to the benzene ring enhances this interaction and forms a more stable glycolipid-CD1d complex.…”

Section: Discussionmentioning

confidence: 99%

“…For example, truncation of the fatty acyl chain or the phytosphingosine group of the glycolipid has been shown to decrease Th1 response (17,18), whereas introduction of an aromatic group to the fatty acyl chain or sphingosine tail has been shown to enhance the production of Th1 cytokines (19,20).…”

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confidence: 99%

Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant

Fujio

Imamura

et al. 2010

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160

201

The glycolipid α-galactosylceramide (α-GalCer) has been shown to bind CD1d molecules to activate invariant natural killer T (iNKT) cells, and subsequently induce activation of various immune-competent cells, including dendritic cells, thereby providing a significant adjuvant effect for various vaccines. However, in phase I clinical trials, α-GalCer was shown to display only marginal biological activity. In our search for a glycolipid that can exert more potent stimulatory activity against iNKT cells and dendritic cells and produce an adjuvant effect superior to α-GalCer, we performed step-wise screening assays on a focused library of 25 α-GalCer analogues. Assays included quantification of the magnitude of stimulatory activity against human iNKT cells in vitro, binding affinity to human and murine CD1d molecules, and binding affinity to the invariant t cell receptor of human iNKT cells. Through this rigorous and iterative screening process, we have identified a lead candidate glycolipid, 7DW8-5, that exhibits a superior adjuvant effect than α-GalCer on HIV and malaria vaccines in mice.

“…It was reported that DT would induce antigen-specific T-cell proliferation and elevate production of IL-2, IFN-γ, and IL-6, suggesting its role in a Th1-driven pathway (41)(42)(43)(44). Despite the fact that the cytokine profile was predominantly Th1, subtypes of anti-DT-associated antibodies were IgG1 with no detectable IgG2a.…”

Section: Search For the Best Epitope Ratio Of Gh-dt/c34 Vaccine And Cmentioning

confidence: 97%

Carbohydrate-based vaccines with a glycolipid adjuvant for breast cancer

Huang

Hung

Cheung

et al. 2013

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141

150

Globo H (GH) is a hexasaccharide specifically overexpressed on a variety of cancer cells and therefore, a good candidate for cancer vaccine development. To identify the optimal carrier and adjuvant combination, we chemically synthesized and linked GH to a carrier protein, including keyhole limpet hemocyanion, diphtheria toxoid cross-reactive material (CRM) 197 (DT), tetanus toxoid, and BSA, and combined with an adjuvant, and it was administered to mice for the study of immune response. Glycan microarray analysis of the antiserum obtained indicated that the combination of GH-DT adjuvanted with the α-galactosylceramide C34 has the highest enhancement of anti-GH IgG. Compared with the phase III clinical trial vaccine, GHkeyhole limpet hemocyanion/QS21, the GH-DT/C34 vaccine elicited more IgG antibodies, which are more selective for GH and the GHrelated epitopes, stage-specific embryonic antigen 3 (SSEA3) and SSEA4, all of which were specifically overexpressed on breast cancer cells and breast cancer stem cells with SSEA4 at the highest level (>90%). We, therefore, further developed SSEA4-DT/C34 as a vaccine candidate, and after immunization, it was found that the elicited antibodies are also IgG-dominant and very specific for SSEA4.carbohydrate vaccine | diphtheria toxin