美国纪念斯隆凯特琳癌症研究所Benjamin D. Greenbaum等研究人员合作发现，癌细胞通过不同机制限制逆转座子表达的免疫原性。2024年11月21日，国际知名学术期刊《免疫》在线发表了这一成果。

研究人员揭示了免疫刺激性重复序列表达、肿瘤演化以及肿瘤免疫微环境之间的关系。对一组胰腺导管腺癌（PDAC）患者的多模态数据整合分析显示，特定的Alu重复序列表达被预测为形成双链RNA（dsRNA），并触发视黄酸诱导基因I（RIG-I）样受体（RLR）相关的I型干扰素（IFN）信号通路。这些来源于Alu的双链RNA还与晚期肿瘤中促肿瘤巨噬细胞的浸润呈负相关。研究人员定义了PDAC适应这种抗肿瘤信号的两种互补途径。

在TP53突变的肿瘤中，长散在核元件（LINE）-1的ORF1p优先结合Alu并降低其表达，而在TP53野生型肿瘤中，作用于RNA的腺苷脱氨酶1（ADAR1）的编辑主要减少双链RNA的形成。敲除LINE-1 ORF1p或ADAR1中的任何一个均在体外减少了肿瘤生长。肿瘤通过多种途径缓解免疫刺激性重复序列的事实表明，其表达所带来的压力是PDAC及可能其他肿瘤适应的一个基本现象。

研究人员表示，为了生存，癌细胞必须应对伴随癌基因转化而来的急性炎症信号，例如重复序列的过度表达。

附：英文原文

Title: Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms

Author: Siyu Sun, Eunae You, Jungeui Hong, David Hoyos, Isabella S. Del Priore, Kaloyan M. Tsanov, Om Mattagajasingh, Andrea Di Gioacchino, Sajid A. Marhon, Jonathan Chacon-Barahona, Hao Li, Hua Jiang, Samira Hozeifi, Omar Rosas-Bringas, Katherine H. Xu, Yuhui Song, Evan R. Lang, Alexandra S. Rojas, Linda T. Nieman, Bidish K. Patel, Rajmohan Murali, Pharto Chanda, Ali Karacay, Nicolas Vabret, Daniel D. De Carvalho, Daniel Zenklusen, John LaCava, Scott W. Lowe, David T. Ting, Christine A. Iacobuzio-Donahue, Alexander Solovyov, Benjamin D. Greenbaum

Issue&Volume: 2024-11-21

Abstract: To thrive, cancer cells must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of repeat elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution, and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNAs (dsRNAs) and trigger retinoic-acid-inducible gene I (RIG-I)-like-receptor (RLR)-associated type-I interferon (IFN) signaling. Such Alu-derived dsRNAs also anti-correlated with pro-tumorigenic macrophage infiltration in late stage tumors. We defined two complementary pathways whereby PDAC may adapt to such anti-tumorigenic signaling. In mutant TP53 tumors, ORF1p from long interspersed nuclear element (LINE)-1 preferentially binds Alus and decreases their expression, whereas adenosine deaminases acting on RNA 1 (ADAR1) editing primarily reduces dsRNA formation in wild-type TP53 tumors. Depletion of either LINE-1 ORF1p or ADAR1 reduced tumor growth in vitro. The fact that tumors utilize multiple pathways to mitigate immunostimulatory repeats implies the stress from their expression is a fundamental phenomenon to which PDAC, and likely other tumors, adapt.

DOI: 10.1016/j.immuni.2024.10.015

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00494-1