Valency and density matter: Deciphering impacts of immunogen structures on immune responses against a tumor associated carbohydrate antigen using synthetic glycopolymers.
Valency and density matter: Deciphering impacts of immunogen structures on immune responses against a tumor associated carbohydrate antigen using synthetic glycopolymers.
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DOI：
10.1016/j.biomaterials.2016.05.050
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发表时间：
2016-09
期刊：
影响因子：
14
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Qin Q;Yin Z;Wu X;Haas KM;Huang X
对于成功的基于碳水化合物的抗癌疫苗，关键是激活B细胞以分泌靶向肿瘤相关碳水化合物抗原（TACA）的抗体。尽管有许多基于TACA的构建体，但缺乏对结构特征对抗聚糖抗体应答的影响的系统理解。在这项研究中，一系列确定的合成糖聚合物带有代表性的TACA，即，已经制备了新的T细胞（Tn）抗原，以探测通过T细胞非依赖性机制诱导早期B细胞活化和抗体产生。聚合物中抗原的价态和密度被证明是关键的。平均每条链需要大于6个Tn来诱导抗体产生。主链分子量为450 kDa、每条链含40个抗原的糖基共聚物在体外对B细胞的刺激作用最强，这与其体内活性密切相关。与所需效价和密度的偏差导致抗体产生减少或甚至抗原特异性B细胞无应答性。这些发现提供了关于如何调节抗TACA免疫应答的重要见解，促进了使用糖共聚物开发基于TACA的抗癌疫苗。抗原之间的化合价和间隔对于产生针对肿瘤相关碳水化合物抗原的抗体是关键的。
For successful carbohydrate based anti-cancer vaccines, it is critical that B cells are activated to secret antibodies targeting the tumor associated carbohydrate antigens (TACAs). Despite the availability of many TACA based constructs, systematic understanding of the effects of structural features on anti-glycan antibody responses is lacking. In this study, a series of defined synthetic glyco-polymers bearing a representative TACA, i.e., the Thomsen-nouveau (Tn) antigen, have been prepared to probe the induction of early B cell activation and antibody production via a T cell independent mechanism. Valency and density of the antigen in the polymers turned out to be critical. An average of greater than 6 Tn per chain was needed to induce antibody production. Glycopolymers with 40 antigens per chain and backbone molecular weight of 450 kDa gave the strongest stimulation to B cells in vitro, which correlated well with its in vivo activity. Deviations from the desired valency and density led to decreased antibody production or even antigen specific B cell non-responsiveness. These findings provide important insights on how to modulate anti-TACA immune responses facilitating the development of TACA based anti-cancer vaccines using glycopolymers. The valency and the spacing between the antigens are critical for antibody generation against a tumor associated carbohydrate antigen.