Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203.
Infectious Disease Division, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203.
J Immunol. 2018 Dec 15;201(12):3750-3758. doi: 10.4049/jimmunol.1801041. Epub 2018 Nov 16.
The tumor microenvironment is rendered immunosuppressive by a variety of cellular and acellular factors that represent potential cancer therapeutic targets. Although exosomes isolated from ovarian tumor ascites fluids have been previously reported to induce a rapid and reversible T cell arrest, the factors present on or within exosomes that contribute to immunosuppression have not been fully defined. In this study, we establish that GD3, a ganglioside expressed on the surface of exosomes isolated from human ovarian tumor ascites fluids, is causally linked to the functional arrest of T cells activated through their TCR. This arrest is inhibited by Ab blockade of exosomal GD3 or by the removal of GD3 exosomes. Empty liposomes expressing GD3 on the surface also inhibit the activation of T cells, establishing that GD3 contributes to the functional arrest of T cells independent of factors present in exosomes. Finally, we demonstrate that the GD3-mediated arrest of the TCR activation is dependent upon sialic acid groups, because their enzymatic removal from exosomes or liposomes results in a loss of inhibitory capacity. Collectively, these data define GD3 as a potential immunotherapeutic target.
肿瘤微环境被多种细胞和无细胞因子所抑制，这些因子代表了潜在的癌症治疗靶点。尽管已经有报道称从卵巢肿瘤腹水中分离出的外泌体可以诱导 T 细胞快速和可逆的阻滞，但对于导致免疫抑制的外泌体上或其中存在的因子尚未完全确定。在这项研究中，我们确定了 GD3，一种在人卵巢肿瘤腹水中分离的外泌体表面表达的神经节苷脂，与通过 TCR 激活的 T 细胞的功能阻滞有因果关系。这种阻滞可以通过 Ab 阻断外泌体 GD3 或去除 GD3 外泌体来抑制。表面表达 GD3 的空脂质体也能抑制 T 细胞的激活，这表明 GD3 独立于外泌体中的因子，对 T 细胞的功能阻滞有贡献。最后，我们证明了 GD3 介导的 TCR 激活阻滞依赖于唾液酸基团，因为它们在外泌体或脂质体中的酶去除导致抑制能力丧失。总的来说，这些数据将 GD3 定义为一个潜在的免疫治疗靶点。
