Intratumoral injection of α-Gal glycolipids induces xenograft-like destruction and conversion of lesions into endogenous vaccines
Intratumoral injection of α-Gal glycolipids induces xenograft-like destruction and conversion of lesions into endogenous vaccines
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DOI：
10.4049/jimmunol.178.7.4676
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发表时间：
2007-04-01
影响因子：
4.4
通讯作者：
Abdel-Motal, Ussama A.
中科院分区：
文献类型：
--
作者：
Galili, Uri;Wigglesworth, Kim;Abdel-Motal, Ussama A.
这项研究描述了一种新型癌症免疫疗法，利用天然抗 Gal 抗体破坏肿瘤病变，并将其转化为通过 Fc gamma R 靶向 APC 的内源性疫苗。抗 Gal 构成人体免疫球蛋白的 1%，并与 a-gal 表位（Gal α 1-3Gal beta 1-4GlcNAc-R）特异性相互作用。抗-Gal 与猪细胞上的 a-gal 表位的结合介导异种移植排斥。所提出的方法使用具有多个 a-gal 表位的糖脂胶束（a-gal 糖脂）。这些糖脂是从兔红细胞膜中提取的，由神经酰胺和含有 5-25 种碳水化合物的碳水化合物链组成，所有碳水化合物均以 a-gal 表位封端。这种治疗的功效在产生抗-Gal并携带B16黑色素瘤或产生OVA作为替代肿瘤Ag的B16/OVA的α1,3-半乳糖基转移酶敲除小鼠中得到证实。这些小鼠在非灵长类哺乳动物中是独一无二的，因为与人类相似，它们缺乏 α-gal 表位，并且可以产生抗 Gal 抗体。瘤内注射α-半乳糖脂会导致抗半乳糖与多个α-半乳糖表位结合并激活补体介导的局部炎症。这些糖脂自发地插入肿瘤细胞膜中。抗-Gal 与表达α-gal 的肿瘤细胞的结合诱导治疗损伤的破坏，如抗-Gal 介导的异种移植排斥一样。抗-Gal 进一步调理病灶内的肿瘤细胞，从而有效地摄取它们。由 APC 将肿瘤 Ag 转运至引流淋巴结。 APC 进一步交叉呈递免疫原性肿瘤 Ag 肽并引发全身抗肿瘤免疫反应。在人体中类似地瘤内注射α-半乳糖糖脂可能会诱导所治疗病灶的破坏，并引发针对微转移的保护性免疫反应。
This study describes a novel cancer immunotherapy treatment that exploits the natural anti-Gal Ab to destroy tumor lesions and convert them into an endogenous vaccine targeted to APC via Fc gamma R. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts specifically with a-gal epitopes (Gal alpha 1-3Gal beta 1-4GlcNAc-R). The binding of anti-Gal to a-gal epitopes on pig cells mediates xenograft rejection. The proposed method uses glycolipid micelles with multiple a-gal epitopes (a-gal glycolipids). These glycolipids are extracted from rabbit red cell membranes and are comprised of ceramides with carbohydrate chains containing 5-25 carbohydrates, all capped with a-gal epitopes. Efficacy of this treatment was demonstrated in alpha 1,3-galactosyltransferase knockout mice producing anti-Gal and bearing B16 melanoma or B16/OVA producing OVA as a surrogate tumor Ag. These mice are unique among nonprimate mammals in that, similar to humans, they lack alpha-gal epitopes and can produce the anti-Gal Ab. Intratumoral injection of alpha-gal glycolipids results in local inflammation mediated by anti-Gal binding to the multiple a-gal epitopes and activation of complement. These glycolipids spontaneously insert into tumor cell membranes. The binding of anti-Gal to alpha-gal expressing tumor cells induces the destruction of treated lesions as in anti-Gal-mediated xenograft rejection. Anti-Gal further opsonizes tumor cells within the lesion and, thus, targets them for effective uptake. by APC that transport the tumor Ags to draining lymph nodes. APC further cross-present immunogenic tumor Ag peptides and elicit a systemic anti-tumor immune response. Similar intratumoral injection of alpha-gal glycolipids in humans is likely to induce the destruction of treated lesions and elicit a protective immune response against micrometastases.