不变的自然杀伤 T 细胞 (iNKT) 细胞响应 α-半乳糖神经酰胺 (α-GalCer) 刺激而产生大量细胞因子。此前发现一种酰基链上含有两个苯环的类似物 C34 比 α-GalCer 更偏向 Th1，并在小鼠体内引发更强的抗乳腺癌、黑色素瘤和肺癌活性。由于肝脏富含 iNKT 细胞，我们研究了 C34 对肝转移神经母细胞瘤的抗癌功效。 C34 诱导肝脏中 Th1 偏向的细胞因子分泌，显着抑制神经母细胞瘤生长/转移并延长小鼠存活时间。抗肿瘤功效可能归因于荷瘤肝脏中肝脏 NKT、NK、CD4 T 和 CD8 T 细胞的更大扩增以及髓源性抑制细胞 (MDSC) 的 SSCloGr1intCD11b 亚群数量的减少小鼠，与 DMSO 对照组相比。 C34 还上调 CD1d 和 CD11c 的表达，特别是在 MDSC 的 SSCloGr1intCD11b 子集中，这些细胞可能会被 C34 激活的 NKT 细胞杀死，因为它们的数量减少。此外，C34 还诱导 CD4 T、CD8 T 和 NK 细胞的扩增，这可能会消除神经母细胞瘤细胞。 C34 的这些免疫调节作用可能在肝脏局部环境中协同作用，抑制肿瘤生长。进一步分析神经母细胞瘤数据库发现，肿瘤单核MDSCs中CD11c高表达的患者生存期较长，提示C34治疗神经母细胞瘤的潜在临床应用。版权所有©2024 The Authors。由 Elsevier Masson SAS 出版。保留所有权利。

Invariant natural killer T cell (iNKT) cells produce large amounts of cytokines in response to α-Galactosylceramide (α-GalCer) stimulation. An analog containing two phenyl rings on the acyl chain, C34, was previously found to be more Th1-biased than α-GalCer and triggered greater anticancer activities against breast cancer, melanoma and lung cancer in mice. Since liver is enriched in iNKT cells, we investigated anticancer efficacy of C34 on neuroblastoma with hepatic metastasis. C34 induced Th1-biased cytokine secretions in the liver, significantly suppressed neuroblastoma growth/metastasis and prolonged mouse survival. The anti-tumor efficacy might be attributed to greater expansions of hepatic NKT, NK, CD4+ T, and CD8+ T cells as well as reduction of the number of SSCloGr1intCD11b+ subset of myeloid-derived suppressor cells (MDSCs) in the liver of tumor-bearing mice, as compared to DMSO control group. C34 also upregulated expression of CD1d and CD11c, especially in the SSCloGr1intCD11b+ subset of MDSCs, which might be killed by C34-activated NKT cells, attributing to their reduced number. In addition, C34 also induced expansion of CD4+ T, CD8+ T, and NK cells, which might eliminate neuroblastoma cells. These immune-modulating effects of C34 might act in concert in the local milieu of liver to suppress the tumor growth. Further analysis of database of neuroblastoma revealed that patients with high CD11c expression in the monocytic MDSCs in the tumor had longer survival, suggesting the potential clinical application of C34 for treatment of neuroblastoma.Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.