Invariant natural killer T (iNKT) cells recognize glycolipid antigens bound to CD1d molecules on antigen-presenting cells. Therapeutic activation of iNKT cells with the xenogeneic glycolipid α-galactosylceramide (α-GalCer) can prevent and reverse tumor growth in murine models, but clinical trials using α-GalCer-stimulated human iNKT cells have shown limited efficacy. We synthesized a series of thioglycoside analogs of α-GalCer with different substituents to the galactose residue and found that two of these compounds, XZ7 and XZ11, bound to CD1d-transfected HeLa cells and activated lines of expanded human iNKT cells. Both compounds stimulated cytolytic degranulation by iNKT cells and while XZ7 preferentially stimulated the production of the antitumor cytokine interferon-γ (IFN-γ), XZ11 preferentially stimulated interleukin-4 (IL-4) production. This biased T helper type 1 effector profile of XZ7 was also evident when iNKT were stimulated with dendritic cells presenting this glycolipid. Separate analysis of the responses of CD4⁺, CD8α⁺ and CD4⁻CD8⁻ iNKT cells indicated that XZ7 preferentially activated CD8α⁺ iNKT cells, and to a lesser degree, CD4⁻CD8⁻ iNKT cells. The partial agonist effect of glycolipid XZ7, inducing cytotoxicity and IFN-γ production but not IL-4 production, indicates that specific protumour activities of iNKT cells can be abolished, while preserving their antitumor activities, by introducing structural modifications to α-GalCer. Since XZ7 was much less potent than α-GalCer as an iNKT cell agonist, it is unlikely to be superior to α-GalCer as a therapeutic agent for cancer, but may serve as a parent compound for developing more potent structural analogs.

中文翻译：

---

α-半乳糖基神经酰胺的新型硫代糖苷类似物刺激人类不变的自然杀伤性T细胞的细胞毒性和Th1细胞因子的优先生产

不变的自然杀伤T（iNKT）细胞识别与抗原呈递细胞上CD1d分子结合的糖脂抗原。用异种糖脂α-半乳糖基神经酰胺（α-GalCer）治疗性激活iNKT细胞可以预防和逆转鼠模型中的肿瘤生长，但是使用α-GalCer刺激的人iNKT细胞进行的临床试验显示出有限的功效。我们合成了一系列具有不同半乳糖残基取代基的α-GalCer硫代糖苷类似物，发现其中两个化合物XZ7和XZ11与CD1d转染的HeLa细胞和扩增的人iNKT细胞的活化细胞系结合。两种化合物均刺激iNKT细胞的溶细胞性脱颗粒作用，而XZ7优先刺激抗肿瘤细胞因子干扰素-γ（IFN-γ）的产生，XZ11优先刺激白介素4（IL-4）的产生。当iNKT被呈现糖脂的树突状细胞刺激时，XZ7的这种偏向性的T辅助1型效应子谱也很明显。CD4响应的单独分析⁺，CD8α ⁺和CD4 ^- CD8 ^- iNKT细胞表明XZ7优先激活CD8α ⁺ iNKT细胞，并在较小程度上激活CD4 ^- CD8 ^- iNKT细胞。糖脂XZ7的部分激动作用，诱导细胞毒性和IFN-γ产生，但不引起IL-4产生，表明iNKT细胞的特定肿瘤活性可以被消除，同时通过对α-GalCer进行结构修饰来保留其抗肿瘤活性。由于XZ7作为iNKT细胞激动剂的效力远不如α-GalCer，因此它不可能优于作为癌症治疗剂的α-GalCer，但可以用作开发更有效的结构类似物的母体化合物。