Expression of down-regulated ERV LTR elements associates with immune activation in human small-cell lung cancers.

IF 4.7 2区 生物学 Q1 GENETICS & HEREDITY Mobile DNA Pub Date : 2023-03-14 DOI:10.1186/s13100-023-00290-w
Marco Russo, Sara Morelli, Giovanni Capranico
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Abstract

Small-cell lung cancer (SCLC) is an aggressive cancer characterized by immunosuppressive features leading to poor responses to current immunotherapies. Activation of transposable elements (TE) can trigger an innate immune response, which can synergize with immunotherapeutic protocols in patients. However, TE activity in relation to immune gene response is not fully known in human SCLC. Here, we compared TE expression in 104 human SCLC and 24 normal tissues and established their involvement in innate immune responses. We observed that different intergenic TEs, mainly endogenous retroviral (ERV) families, are deregulated in SCLC. Similarly to other cancers, we detected a subset of LTRs that correlate with innate immune gene signatures and cytosolic RNA sensors, such as RIG-I. These LTRs are downregulated in SCLC tumors vs. normal tissues, and are mainly located at transcriptional repressed regions, marked with H3K4me2 in different cell lines. Analyses of different genomic datasets show that chromatin repression is likely due to de-methylase LSD1 activity. Moreover, high expression levels of ERV LTRs predict a better survival upon chemotherapy of SCLC patients. The findings reveal a specific pattern of TE-mediated activation of innate immune genes in SCLC, which can be exploited to establish more effective immunotherapeutic combinations.

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下调ERV LTR元件的表达与人小细胞肺癌的免疫激活相关。
小细胞肺癌(SCLC)是一种侵袭性癌症,其特征是免疫抑制,导致对当前免疫疗法的反应较差。转座因子(TE)的激活可以触发先天免疫反应,这可以与患者的免疫治疗方案协同作用。然而,TE活性与免疫基因反应的关系在人类SCLC中尚不完全清楚。在这里,我们比较了104例人类SCLC和24例正常组织中的TE表达,并确定了它们参与先天免疫反应。我们观察到不同的基因间te,主要是内源性逆转录病毒(ERV)家族,在SCLC中被解除调控。与其他癌症类似,我们检测到与先天免疫基因特征和细胞质RNA传感器(如rig - 1)相关的ltr子集。与正常组织相比,这些LTRs在SCLC肿瘤中下调,主要位于转录抑制区,在不同细胞系中以H3K4me2标记。对不同基因组数据集的分析表明,染色质抑制可能是由于去甲基化酶LSD1的活性。此外,ERV LTRs的高表达水平预示着SCLC患者化疗后更好的生存。研究结果揭示了te介导的SCLC先天免疫基因激活的特定模式,这可以用来建立更有效的免疫治疗组合。
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来源期刊
Mobile DNA
Mobile DNA GENETICS & HEREDITY-
CiteScore
8.20
自引率
6.10%
发文量
26
审稿时长
11 weeks
期刊介绍: Mobile DNA is an online, peer-reviewed, open access journal that publishes articles providing novel insights into DNA rearrangements in all organisms, ranging from transposition and other types of recombination mechanisms to patterns and processes of mobile element and host genome evolution. In addition, the journal will consider articles on the utility of mobile genetic elements in biotechnological methods and protocols.
期刊最新文献
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