Mac-1的结构与功能及其在肿瘤免疫治疗中的作用

Structure and function of Mac-1 and its role in cancer immunotherapy

Mac-1是位于白细胞表面参于机体防御作用及免疫反应的重要的粘附分子,它由α(CD11b)和β(CD18)两个亚基以非共价键的方式缔合成异二聚体,Mac-1的分子结构中有两个重要的区域:一个是识别蛋白配体的I-域,另一个是识别多糖的凝集素部位。Mac-1在几乎所有中性粒细胞、单核细胞、嗜酸性细胞和NK细胞上广泛表达,巨噬细胞、B细胞和T细胞表达较少。Mac-1具有两种主要的功能:一是与活化的内皮细胞表面上的ICAM-1高亲和力的粘附,介导白细胞的游走与渗出。二是作为iC3b的受体,介导白细胞对iC3b调理的微生物或靶细胞的细胞毒功能。此外,Mac-1还能与许多细胞膜表面的糖蛋白缔合成复合物,介导信号的跨膜转导。研究发现,可溶性的β-葡聚糖能够结合并致敏Mac-1继而触发吞噬细胞或NK细胞对iC3b-调理的肿瘤细胞的细胞毒反应,这一发现为β-葡聚糖在肿瘤免疫治疗中的应用提供了理论基础。大多数的人类或动物的肿瘤细胞能活化补体并在原位被iC3b调理,肿瘤细胞表面的iC3b结合到β-葡聚糖致敏了的Mac-1后,吞噬细胞或NK细胞就能杀伤肿瘤细胞。

Mac-1, an adhesion molecule expressed on the surface of leukocytes, plays an important role in host-defence function and immunological response. It consists of two noncovalently linked polypeptides known as α（ CD111b） and β（CD18） subunits. It contains two important domains known as l-domain which recognizes protein ligands and the lectin domain which recognizes polysaccharides. Mac-1 is expressed on nearly all neutrophils, monocytes, eosinophils and NK cells, but less on B cells, T cells and macrophages. Mac-1 functions as both an adhesion molecule for ICAM-1 expressed by stimulated endothelium mediating the diapedesis of leukocytes across the endothelium and a receptor for the iC3b fragment of complement responsible for cytotoxicity to microorganisms or target ceils opsonized with iC3b. It can also form a complex with many membrane glycoproteins, functioning as a signal transducing partner for them. An important finding was that soluble β-glucan could bind to Mac-1 and prime the receptor for cytotoxic function in response to iC3b-opsonized tumors, thus may pave the way for development of β-gh.can-like drugs that could generate Mac-1-dependent cytotoxicity following a humoral response to tumor antigens elicited by vaccines that would cause tumors to be opsonized with Abs and iC3b in cancer immunotherapy.