Department of Immunology, Mayo Clinic, Rochester, MN; and.
Department of Urology, College of Medicine, Mayo Clinic, Rochester, MN.
J Immunol. 2022 Apr 15;208(8):1845-1850. doi: 10.4049/jimmunol.2101165. Epub 2022 Apr 4.
Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells that recognize specific sialic acid modifications on cell surface glycans. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered immune responses and increased tumor growth. In this study, we examined the role of ST8Sia6 on immune cells in regulating antitumor immunity. ST8Sia6 knockout mice had an enhanced immune response to tumors. The loss of ST8Sia6 promoted an enhanced intratumoral activation of macrophages and dendritic cells, including upregulation of CD40. Intratumoral regulatory T cells exhibited a more inflammatory phenotype in ST8Sia6 knockout mice. Using adoptive transfer studies, the change in regulatory T cell phenotype was not cell intrinsic and depended on the loss of ST8Sia6 expression in APCs. Thus, ST8Sia6 generates ligands for Siglecs that dampen antitumor immunity.
抑制性受体在免疫调节中起着关键作用。Siglecs 是一类主要的抑制性受体，表达于免疫细胞上，能够识别细胞表面糖链上特定的唾液酸修饰。许多肿瘤中唾液酸的含量增加。肿瘤中唾液酸转移酶 ST8Sia6 的过度表达导致免疫反应改变和肿瘤生长增加。在这项研究中，我们研究了 ST8Sia6 对免疫细胞在调节抗肿瘤免疫中的作用。ST8Sia6 敲除小鼠对肿瘤的免疫反应增强。ST8Sia6 的缺失促进了肿瘤内巨噬细胞和树突状细胞的激活，包括 CD40 的上调。肿瘤内调节性 T 细胞在 ST8Sia6 敲除小鼠中表现出更具炎症表型。通过过继转移研究，调节性 T 细胞表型的改变不是细胞内在的，而是依赖于 APC 中 ST8Sia6 表达的缺失。因此，ST8Sia6 产生 Siglec 的配体，从而抑制抗肿瘤免疫。
