K27M-mutant histone-3 as a novel target for glioma immunotherapy.
K27M-mutant histone-3 as a novel target for glioma immunotherapy.
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DOI：
10.1080/2162402x.2017.1328340
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
Platten M
中科院分区：
文献类型：
--
作者：
Ochs K;Ott M;Bunse T;Sahm F;Bunse L;Deumelandt K;Sonner JK;Keil M;von Deimling A;Wick W;Platten M
突变特异性疫苗在神经胶质瘤免疫治疗中越来越重要；然而，共享的新表位是罕见的。对于弥漫性胶质瘤，异柠檬酸脱氢酶1型基因的驱动突变已被证明可产生目前临床试验中靶向的免疫原性表位。对于高度侵袭性中线胶质瘤，组蛋白3基因（H3F3A）的复发点突变导致27号位置（K27M）的氨基酸从赖氨酸变为蛋氨酸。在这里，我们证明了针对k27m突变组蛋白3的肽疫苗能够在主要组织相容性复合体（MHC）人源化小鼠模型中诱导有效的、突变特异性的、细胞毒性的t细胞和t辅助细胞介导的免疫反应。通过证明H3K27M驱动突变H3K27M在人类H3K27M突变胶质瘤MHC II类上的免疫有效表现，我们的数据为进一步临床开发基于疫苗或基于细胞的H3K27M免疫治疗方法提供了基础。
Mutation-specific vaccines have become increasingly important in glioma immunotherapy; however, shared neoepitopes are rare. For diffuse gliomas, a driver mutation in the gene for isocitrate dehydrogenase type-1 has been shown to produce an immunogenic epitope currently targeted in clinical trials. For highly aggressive midline gliomas, a recurrent point mutation in the histone-3 gene (H3F3A) causes an amino acid change from lysine to methionine at position 27 (K27M). Here, we demonstrate that a peptide vaccine against K27M-mutant histone-3 is capable of inducing effective, mutation-specific, cytotoxic T-cell- and T-helper-1-cell-mediated immune responses in a major histocompatibility complex (MHC)-humanized mouse model. By proving an immunologically effective presentation of the driver mutation H3K27M on MHC class II in human H3K27M-mutant gliomas, our data provide a basis for the further clinical development of vaccine-based or cell-based immunotherapeutic approaches targeting H3K27M.