Russo Marco, Morelli Sara, Capranico Giovanni
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, via Selmi 3, 40126, Bologna, Italy.
Mob DNA. 2023 Mar 14;14(1):2. doi: 10.1186/s13100-023-00290-w.
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.
小细胞肺癌（SCLC）是一种侵袭性癌症，具有免疫抑制特征，导致对当前免疫疗法反应不佳。转座元件（TE）的激活可触发先天性免疫反应，这可与患者的免疫治疗方案协同作用。然而，在人类SCLC中，TE活性与免疫基因反应的关系尚不完全清楚。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，并确定了它们在先天性免疫反应中的作用。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中失调。与其他癌症类似，我们检测到一部分与先天性免疫基因特征和胞质RNA传感器（如RIG-I）相关的长末端重复序列（LTR）。这些LTR在SCLC肿瘤中相对于正常组织下调，并且主要位于转录抑制区域，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 LTR的高表达水平预示着SCLC患者化疗后的生存期更好。这些发现揭示了SCLC中TE介导的先天性免疫基因激活的特定模式，可利用该模式建立更有效的免疫治疗组合。
