Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia.
Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia.
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DOI：
10.1158/2326-6066.cir-16-0280
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发表时间：
2017-05
影响因子：
10.1
通讯作者：
Cobbold M
中科院分区：
文献类型：
--
作者：
Malaker SA;Penny SA;Steadman LG;Myers PT;Loke JC;Raghavan M;Bai DL;Shabanowitz J;Hunt DF;Cobbold M
白血病是高度免疫原性的，但具有低突变负荷，提供很少的突变肽靶标。因此，识别替代新抗原是一项迫切的需要。在这里，我们使用三种实验方法鉴定了36种具有O-连接的β-N-乙酰葡萄糖胺（O-GlcNAc）修饰的MHC I类相关肽抗原作为候选新抗原。这些肽中的13个也被检测到在相同的残基上具有二糖单元，并且两个含有单甲基化和/或二甲基化精氨酸残基。一个子集与关键的癌症途径相关，并且这些肽在所有测试的白血病患者样本中共享（5/5）。合成了七种O-GlcNAc肽，其中五种（71%）与健康供体的多功能记忆T细胞反应有关。O-GlcNAc特异性T细胞系特异性杀伤用修饰肽脉冲的自体细胞，但不杀伤等效的未修饰肽。因此，这些免疫后修饰的新抗原为癌症免疫治疗提供了合理的靶标。
Leukemias are highly immunogenic but have a low mutational load, providing few mutated peptide targets. Thus, the identification of alternative neoantigens is a pressing need. Here, we identify 36 MHC class I–associated peptide antigens with O-linked β-N-acetylglucosamine (O-GlcNAc) modifications as candidate neoantigens, using three experimental approaches. Thirteen of these peptides were also detected with disaccharide units on the same residues and two contain either mono- and/or di-methylated arginine residues. A subset were linked with key cancer pathways, and these peptides were shared across all of the leukemia patient samples tested (5/5). Seven of the O-GlcNAc peptides were synthesized and five (71%) were shown to be associated with multifunctional memory T-cell responses in healthy donors. An O-GlcNAc-specific T-cell line specifically killed autologous cells pulsed with the modified peptide, but not the equivalent unmodified peptide. Therefore, these post-translationally modified neoantigens provide logical targets for cancer immunotherapy.