A Designed α‐GalCer Analog Promotes Considerable Th1 Cytokine Response by Activating the CD1d‐iNKT Axis and CD11b‐Positive Monocytes/Macrophages

Abstract

Selective helper T cell 1 (Th1) priming agonists are a promising area of investigation for immunotherapeutic treatment of various diseases. α ‐galactosylceramide ( α ‐GalCer, KRN7000), a well‐studied Th1‐polarizer, simultaneously induces helper T cell 2 (Th2)‐type responses, which is a major drawback for its clinical applications. Based on surflex‐docking computation, α ‐GalCer‐diol, with added hydroxyl groups in the acyl chain, is designed and synthesized. Structural analyses reveal stronger affinity between α ‐GalCer‐diol and cluster of differentiation 1d (CD1d), leading to enhanced antigen presentation by dendritic cells (DCs) and self‐activation, as reflected by tight binding of the T‐cell receptor (TCR)/KRN7000/CD1d ternary complex and elevated production of interleukin 12 (IL‐12) and interferon‐ γ (IFN‐ γ ). Consequently, invariant natural killer T cells (iNKTs) are activated and exhibit an improved Th1‐type cytokine profile ex vivo and in vivo. Different from KRN7000, α ‐GalCer‐diol markedly boosts the expansion of the CD11b + subpopulation and enhances IFN‐ γ content in CD11b + cells. These reinforced Th1‐type responses collectively endow α ‐GalCer‐diol more robust antitumor activity in a xenograft animal model using B16‐F10 melanoma cells. Together, the data demonstrate a new mechanism through which α ‐GalCer‐diol induces stronger Th1‐type responses by stimulating CD11b + leukocyte expansion and DC‐conducted CD1d‐restricted and TCR‐mediated iNKT activation. Hence, this study may facilitate the development of novel Th1 priming agonists.

New insights into iNKT cells and their roles in liver diseases

“…( 29 )reported that threitolceramide- (ThrCer-) induced activation of NKT cells. In addition, researchers have managed to createα-GalCer analogues artificially, including α-GalCer-diol (with added hydroxyl groups in the acyl chain compared to α-GalCer, Juan Ma et al., 2020) ( 30 )and6′-modified α-GalCer analogues (Matthias Trappeniers et al., 2008) ( 31 ). Hopefully, with careful design, these analogues will be applicable as preventative and therapeutic vaccine adjuvants ( 32 , 33 ).…”

The Role of Toll-like Receptor Agonists and Their Nanomedicines for Tumor Immunotherapy

“…The mode of action of α-Galcer is largely due to its strong binding to differentiated clusters (CD1d), members of the CD1 family that express glycoproteins on the plasma membrane of antigen-presenting cells (APCs), such as dendritic cells (DCs). When the α-Galcer-CD1d complex is presented to the semi-invariant T cell receptor (TCR) on immutable natural killer T cells (iNKTs), a ternary complex is formed, leading to the secretion of various cytokines [122]. More recently, Sainz et al combined the NKT agonist α-GalCer, melanoma-associated peptide antigens as well as TLR ligands CpG and MPLA with nanoparticles, which promoted DC maturation, consequently leading to the up-regulation of co-stimulatory markers, such as CD80/CD86, and the production of IL-12/CCL17.…”

“…to the secretion of various cytokines [122]. More recently, Sainz et al combined the NKT agonist α-GalCer, melanoma-associated peptide antigens as well as TLR ligands CpG and MPLA with nanoparticles, which promoted DC maturation, consequently leading to the up-regulation of co-stimulatory markers, such as CD80/CD86, and the production of IL-12/CCL17.…”

IGSF6 is a biomarker associated with anti-tumor immune response in lung adenocarcinoma

“…Antigen peptide-MHCII complex presented by professional antigen presenting cells (APCs) including DCs, macrophages and B cells is essential for the activation of Th1 cells [23][24][25]. The above correlation and enrichment analyses identi ed that IGSF6 was strongly linked with MHCII complex and might participate in antigen uptake by macrophages and DCs through acting as a co-receptor.…”