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

Juan Ma; Peng He; Chuanfang Zhao; Quanzhong Ren; Zheng Dong; Jiahuang Qiu; Yang Jing; Sijin Liu; Yuguo Du

doi:10.1002/advs.202000609

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

Adv Sci (Weinh). 2020 Jun 8;7(14):2000609. doi: 10.1002/advs.202000609. eCollection 2020 Jul.

Authors

Juan Ma^{1

2}, Peng He^{1

3}, Chuanfang Zhao^{1

3}, Quanzhong Ren^{1

2}, Zheng Dong^{1

2}, Jiahuang Qiu^{1

2}, Yang Jing^{1

4}, Sijin Liu^{1

2}, Yuguo Du^{1

3}

Affiliations

¹ State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental Sciences Chinese Academy of Sciences Beijing 100085 P. R. China.
² School of Environmental Sciences University of Chinese Academy of Sciences Beijing 100049 P. R. China.
³ School of Chemical Sciences University of Chinese Academy of Sciences Beijing 100049 P. R. China.
⁴ National Engineering Research Center for Carbohydrate Synthesis Jiangxi Normal University Nanchang Jiangxi 330022 China.

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.

Keywords: CD11b monocytes; CD1d; Th1‐biased immune responses; antitumor activity; α‐GalCer analogs.