Immunoreceptors del Sistema Innat i Adaptatiu, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, Spain.
Immunoreceptors del Sistema Innat i Adaptatiu, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, Spain
J Immunother Cancer. 2020 Mar;8(1). doi: 10.1136/jitc-2019-000172.
CD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6-mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor.
High sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckEμTg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins.
Through a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells.
Evidence is provided for the disruption of CD6 receptor-ligand interactions as a feasible immunomodulatory approach in cancer.
CD6 是一种淋巴细胞表面共受体，与 T 细胞受体 (TCR)/CD3 复合物在免疫突触的中心物理相关联。在那里，CD6 通过与 CD166/ALCAM（活化白细胞细胞黏附分子）相互作用，协助细胞间接触的稳定和激活/分化事件的调节，这是其主要报道的配体。虽然越来越多的证据表明 CD6 作为治疗自身免疫疾病的靶点具有新的意义，但对于其在癌症中的潜在作用知之甚少。为了阐明阻断 CD6 介导的相互作用在健康和疾病中的体内相关性，我们探索了表达高水平循环可溶性 CD6 (sCD6) 作为诱饵受体的后果。
通过使用在淋巴特异性转录元件控制下表达人 sCD6 的转基因 C57BL/6 小鼠（shCD6LckEμTg）或野生型小鼠（经转导编码小鼠 sCD6 的嗜肝腺相关病毒或接受重组人 sCD6 蛋白的多次输注）来实现高 sCD6 血清水平。通过体外流式细胞术和小鼠淋巴器官细胞的功能分析来描述 sCD6 诱导的变化。通过用同源癌细胞诱导的皮下或转移性肿瘤挑战小鼠来探索这些变化的体内相关性。
通过体外和体内研究的结合，我们表明循环 sCD6 的表达诱导了调节性 T 细胞 (Treg) 的生成和功能缺陷、CD166/ALCAM 介导的肿瘤细胞增殖/迁移减少以及半乳糖凝集素诱导的 T 细胞凋亡受损，支持 sCD6 调节抗肿瘤淋巴细胞效应功能和肿瘤发生的事实。因此，体内表达 sCD6 导致在挑战小鼠用同源癌细胞时，皮下肿瘤生长延迟和/或转移减少。
提供了证据表明，破坏 CD6 受体-配体相互作用是癌症中可行的免疫调节方法。
