Oncogenic roles of young human de novo genes and their potential as neoantigens in cancer immunotherapy.

IF 11.1 Q1 CELL BIOLOGY
Chunfu Xiao, Xiaoge Liu, Peiyu Liu, Xinwei Xu, Chao Yao, Chunqiong Li, Qi Xiao, Tiannan Guo, Li Zhang, Yongjun Qian, Chao Wang, Yiting Dong, Yingxuan Wang, Zhi Peng, Chuanhui Han, Qiang Cheng, Ni A An, Chuan-Yun Li
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引用次数: 0

Abstract

Young human de novo genes, recently emerging from non-coding regions, are expected to contribute to human-specific traits and diseases. However, systematic explorations of this connection have been lacking. Here, we report 37 recently originated de novo genes in humans, with their evolution and characteristics defined within an updated genomic context. The expression of these genes is significantly upregulated and temporospatially expanded in tumors, partially associated with extrachromosomal DNA amplification. Depletion of 57.1% of these genes suppresses tumor cell proliferation, underscoring their roles in tumorigenesis. As a proof of concept, we developed mRNA vaccines expressing ELFN1-AS1 and TYMSOS-young genes specifically expressed during early development but reactivated exclusively in tumors. In humanized mice, these vaccines triggered specific T cell activation and inhibited tumor growth. The antigens derived from these genes are immunogenic and capable of eliciting antigen-specific T cell activation in colorectal cancer patients. These findings underscore young human de novo genes as neoantigens in cancer immunotherapy.

年轻人类新生基因的致瘤作用及其在癌症免疫治疗中作为新抗原的潜力。
最近从非编码区出现的年轻的人类新生基因,预计将有助于人类特有的特征和疾病。然而,对这种联系的系统探索一直缺乏。在这里,我们报告了37个最近在人类中起源的新生基因,以及它们在最新基因组背景下的进化和特征。这些基因的表达在肿瘤中显著上调和时空扩展,部分与染色体外DNA扩增有关。这些基因中57.1%的缺失抑制肿瘤细胞增殖,强调了它们在肿瘤发生中的作用。作为概念的证明,我们开发了表达ELFN1-AS1和TYMSOS-young基因的mRNA疫苗,这些基因在早期发育期间特异性表达,但只在肿瘤中被重新激活。在人源化小鼠中,这些疫苗触发特异性T细胞活化并抑制肿瘤生长。来自这些基因的抗原具有免疫原性,能够在结直肠癌患者中引发抗原特异性T细胞活化。这些发现强调了年轻的人类新生基因在癌症免疫治疗中的新抗原作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
7.10
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