Sialyl-tn in cancer: (how) did we miss the target?
Sialyl-tn in cancer: (how) did we miss the target?
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DOI：
10.3390/biom2040435
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发表时间：
2012-10-11
期刊：
影响因子：
5.5
通讯作者：
Delannoy P
中科院分区：
文献类型：
--
作者：
Julien S;Videira PA;Delannoy P
唾液酸化Tn抗原是一种含有唾液酸残基α2，6-的短链O-糖链，与GalNAcα-O-Ser/Thr连接。STN的生物合成是由一种称为ST6GalNAc I的特殊唾液酸基转移酶介导的，它与延伸糖基转移酶的O-糖链竞争，防止癌细胞展示更长的O-糖链。虽然STN在胎儿和正常成人组织中弱表达，但在超过80%的人类癌症中表达，在所有病例中，STN的检测都与患者的不良结局和总生存率下降有关。由于其泛癌表达与不良结果相关，一种名为Theratope的抗癌疫苗已针对STN表位设计。尽管人们对这种免疫疗法热情高涨，但Theratope在第三阶段临床试验中失败了。然而，与其错过这一目标，人们应该考虑修改Theratope的设计和实际情况。在这篇综述中，我们强调了从免疫学角度以及从药物设计和配方以及患者选择中可以学到的许多教训。此外，针对其他碳水化合物抗原和STN载体蛋白(如MUC1)的新型免疫疗法正在产生一个无可辩驳的知识，这将为未来开发更成功的抗STN免疫治疗策略提供保证。
Sialyl-Tn antigen (STn) is a short O-glycan containing a sialic acid residue α2,6-linked to GalNAcα-O-Ser/Thr. The biosynthesis of STn is mediated by a specific sialyltransferase termed ST6GalNAc I, which competes with O-glycans elongating glycosyltransferases and prevents cancer cells from exhibiting longer O-glycans. While weakly expressed by fetal and normal adult tissues, STn is expressed by more than 80% of human carcinomas and in all cases, STn detection is associated with adverse outcome and decreased overall survival for the patients. Because of its pan-carcinoma expression associated with an adverse outcome, an anti-cancer vaccine, named Theratope, has been designed towards the STn epitope. In spite of the great enthusiasm around this immunotherapy, Theratope failed on Phase III clinical trial. However, in lieu of missing this target, one should consider to revise the Theratope design and the actual facts. In this review, we highlight the many lessons that can be learned from this failure from the immunological standpoint, as well as from the drug design and formulation and patient selection. Moreover, an irrefutable knowledge is arising from novel immunotherapies targeting other carbohydrate antigens and STn carrier proteins, such as MUC1, that will warrantee the future development of more successful anti-STn immunotherapy strategies.