Researchers have found that a long noncoding RNA, whose function was previously unknown, turns out to play an important role in promoting the body’s immune response against cancer.
Major histocompatibility complex-I (MHC-I) plays a key role in CD8+ T-cell priming and activation. It specifically presents tumour antigens to CD8+ T-cells and triggers an anti-tumour immune response. Unfortunately, MHC-I is frequently downregulated in cancer cells. This results in tumour immune evasion and resistance to immunotherapies, such as checkpoint blockades, that harness this system. Understanding this process is important to recover tumour MHC-I expression and revive the anti-tumour response.
Long noncoding RNAs (lncRNAs) regulate protein-coding genes at multiple levels. They also have critical roles in genomic imprinting, cell differentiation and cancer progression. With advances in deep RNA sequencing, our ability to detect more lncRNAs is improving. Estimates indicate that humans may have 30,000-60,000 lncRNAs. However, the function and clinical relevance of specific lncRNAs in cancer immunity and immunotherapy remains poorly understood.
An immunogenic long noncoding RNA
In this study, published in Nature Cell Biology, researchers compared cancers with low levels of T-cell infiltration to those with high infiltration. Here, the researchers identified a lncRNA – lncRNA inducing MHC-I and immunogenicity of tumour (LIMIT) – in humans and mice. They found that LIMIT is a cancer immunogenic lncRNA that affects MHC-I machinery and anti-tumour immunity.
When stimulated by IFNγ, LIMIT locally targeted guanylate-binding proteins (GBPs). This formed a cascade of events that ultimately resulted in the activation of heat shock factor-1 (HSF1) and transcription of MHC-I machinery. Using CRISPR techniques, researchers also activated LIMIT and found it boosted checkpoint therapy against tumours in mouse models. Whereas, when the team silenced LIMIT, the immunotherapy was less effective. This suggests that the LIMIT-GBP-HSF1 axis may be targetable by researchers for cancer immunotherapy.
Senior study author Weiping Zou, stated:
“Very often, there is a loss of MHC-I and interferon gamma signalling in human tumours, which helps the cancer evade the immune system.
Our research suggests several new potential therapeutic approaches to overcome this. These include using CRISPR to activate LIMIT and improve MHC-I expression to boost the body’s immune response, and also targeting some of the downstream players in this signalling axis, like GBPs.”
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