Abstract

Background

Endogenous retroelements are a main source of targetable tumor-specific antigens that have the potential to augment host adaptive antitumor responses. KLRC3 gene encodes for the NKG2E and NKG2H isoforms of NKG2 family of transmembrane receptors. Current data support that NKG2E represents the main protein isoform.

Methods

Genome, mobilome and molecular evolutionarily analysis were performed through the corresponding tracks of UCSC Genome Browser Database. NKG2E protein expression data were downloaded from the Human Protein Atlas. NetMHCII 2.3 was used to predict MHC class II binding scores.

Results

In normal tissues, NKG2E protein is scarcely expressed in a rare subset of immune cells in the intestinal tract and lymphoid tissue. Vice versa, in tumor tissues NKG2E expression is detected in > 75% of tumor cells in cases of liver, breast and ovarian cancer as well as in 25-75% of tumor cells in cases of thyroid, stomach and prostate cancer. NKG2E protein is encoded by the long isoform of KLRC3 gene. The last exon of this mRNA is derived via an Alu-element exonization, which provides the last 14 aa of the coding region. Previous analysis showed that the 14 aa Alu-peptide is hydrophobic and impels the intracellular retention of NKG2E protein thereby impeding its function as a transmembrane receptor. A previous study revealed the presence of highly-specific IgG autoantibodies against the Alu-peptide in a disease known to stimulate Alu RNAs overexpression, but not in healthy individuals. The latter signifies not only a high immunogenicity but also that the host is mostly immunologically ignorant rather than tolerant of the Alu-peptide. Accordingly NetMHCII analysis identifies the Alu-peptide as a HLA-DRB1_0103 and -DRB1_1101 high binder.

Conclusion

NKG2E protein represents an aberrant molecule that is misexpressed in multiple cancers, including immunologically “cold” tumor types. Characterization of the rare immune cells producing the aberrant NKG2E molecule in normal tissues warrants further research. Subsequent studies could inquire into a TCD4-specific TCR usage that would allow for the inoculation of cancer patients with autologous CD4-T cells reactive against the Alu-peptide.

Legal entity responsible for the study

Spyros I. Papamichos.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

中文翻译：

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148P NKG2E包含一种衍生自alu-retrotransposon的免疫原性肽：一种有吸引力的新型免疫治疗靶标

抽象的

背景

内源性逆转录酶是可靶向的肿瘤特异性抗原的主要来源，其具有增强宿主适应性抗肿瘤反应的潜力。KLRC3基因编码跨膜受体NKG2家族的NKG2E和NKG2H亚型。当前数据支持NKG2E代表主要的蛋白质同工型。

方法

通过UCSC基因组浏览器数据库的相应路径，进行了基因组，运动组和分子进化分析。NKG2E蛋白表达数据从人类蛋白图谱下载。使用NetMHCII 2.3预测II类MHC结合得分。

结果

在正常组织中，NKG2E蛋白很少在肠道和淋巴组织的免疫细胞的罕见子集中表达。反之亦然，在肝癌，乳腺癌和卵巢癌病例中，在肿瘤组织中检测到NKG2E表达的> 75％，而在甲状腺癌，胃癌和前列腺癌中，则在肿瘤细胞的25％至75％中检测到NKG2E表达。NKG2E蛋白由KLRC3基因的长同种型编码。该mRNA的最后一个外显子是通过Alu元素外显子化得到的，它提供了编码区的最后14个氨基酸。先前的分析表明，14个氨基酸的Alu肽具有疏水性，可促进NKG2E蛋白在细胞内的滞留，从而阻碍其作为跨膜受体的功能。先前的研究表明，在已知会刺激Alu RNA过表达的疾病中存在针对Alu肽的高度特异性IgG自身抗体，而在健康个体中则没有。后者不仅表示高免疫原性，而且还表示宿主对Alu肽在免疫学上大多是免疫无知的，而不是耐受的。因此，NetMHCII分析将Alu肽鉴定为HLA-DRB1_0103和-DRB1_1101高结合剂。

结论

NKG2E蛋白代表在多种癌症（包括免疫“冷”肿瘤类型）中表达异常的异常分子。正常组织中会产生异常NKG2E分子的稀有免疫细胞的特征值得进一步研究。随后的研究可能会询问特定于TCD4的TCR的用法，该用法将允许癌症患者接种对Alu肽具有反应性的自体CD4-T细胞。

负责研究的法人实体

Spyros I. Papamichos。

资金

尚未收到任何资金。

揭露

作者宣称没有利益冲突。