01
DOI: 10.1016/j.ccell.2024.10.014
02
Cancer cells must navigate a balance between their oncogenic potential and the immunogenic costs they incur. Their findings indicate that various types of retrotransposons can have both pro- and anti-tumor effects. Specifically, immunostimulatory SINEs, particularly from the AluY and AluS families, appear to promote anti-tumor activity through RIG-I like receptors such as MDA5, which activate interferon gene pathways. However, "viral mimicry" caused by double-stranded RNA from IR-Alus may be detrimental to tumors and needs to be suppressed. They propose that cancer cells adapt by managing immunostimulatory Alus through convergent evolutionary strategies across different genetic contexts. One mechanism involves L1 activity in mutant TP53 backgrounds that suppresses these Alus, enhancing tumor fitness via immune evasion. In tumors with compromised TP53 function, new L1 insertions often increase, while those with wild-type TP53 rely on ADAR1-mediated RNA editing to neutralize Alu-derived dsRNA. In late-stage grade-4 tumors, they observed a correlation between increased M2 macrophage signals and higher ORF1p levels alongside reduced immunostimulatory Alu expression, suggesting a shift from anti- to pro-tumor signaling linked to L1 activity. This dynamic reshaping appears later in tumor development and is supported by lower CD8+ T cell infiltration when ORF1p levels are high. Their study also reveals that derepressed Alus can stimulate interferon production via dsRNA viral mimics activating RIG-I/MDA5 before changes in p53 function occur. Following alterations in TP53 function, increased L1 translation may help mitigate the effects of immunostimulatory Alus. Overall, their research highlights the complex interplay of retrotransposons in shaping the immune landscape of tumors and suggests potential avenues for precision therapies targeting specific genetic contexts related to TP53 mutations and retrotransposition activities.
DOI: 10.1016/j.immuni.2024.10.015
关注我们获取更多免疫学文献资讯
Editor & Reviewer: Congci Yu
