A Designed ?-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. ?-galactosylceramide (?-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, ?-GalCer-diol, with added hydroxyl groups in the acyl chain, is designed and synthesized. Structural analyses reveal stronger affinity between ?-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-? (IFN-?). 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, ?-GalCer-diol markedly boosts the expansion of the CD11b+ subpopulation and enhances IFN-? content in CD11b+ cells. These reinforced Th1-type responses collectively endow ?-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 ?-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.

SUBMITTER: Ma J 

PROVIDER: S-EPMC7375225 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature