Adar Gene Interference for Cancer Immunotherapy

The adenosine deaminase acting on RNA (ADAR) enzymes that have been identified to specifically recognizes and edits double-stranded RNA (dsRNA), catalyze the Adenosine-to-Inosine (A-to-I) RNA editing. They are widely expressed in most of higher eukaryotes, where tens of thousands of posttranscriptional editing of A-to-I conversions happen in inverted repeats that form long dsRNAs such as the Alu element. In the ADAR family, there’re catalytically active enzymes including ADAR1, ADAR2 and the inactive ADAR3. While ADAR2’s specific substrates are mainly in the brain tissue, ADAR1 is more ubiquitously expressed, and function as the primary editing enzyme converting A-to-I mutation. Since the inherent translational machinery reads inosine as guanosine, ADAR1 mediated A-to-I RNA editing results in non-synonymous coding changes (A-to-G mutation) (Yeo et al., 2010), potentially altering the protein encoded by the mRNA. Additionally, ADAR1 can also modulate microRNA pathways independent of its editing activity, employed only as the dsRNA binding protein without editing function. Mounting evidence indicates that the level of dsRNA recognition and editing by Adar1 plays an important role in restraining autoimmunity activity and maintaining self-tolerance, in which RNA editing is pivotal for controlling the cytoplasmic antiviral immunity. Intriguingly, mutations in humans and in mice models in ADAR1 can induce autoimmunity[1] and ADAR1 has recently been shown to regulate the canonical RNA sensing pathways such as RIG-I-like receptors (retinoic acid-inducible gene-I-like receptors, RLRs) and protein kinase R (PKR) [2-4]. ADAR1 was demonstrated to leverage the sensing of endogenous dsRNA level, allowing for detection of pathogen while avoiding autoinflammation. It’s reported that when the “self” endogenous dsRNAs are not edited sufficiently by ADAR1, which would be recognized as “non- self” pathogenic dsRNAs by the dsRNA sensor MDA5 to trigger an innate immune response to lower the cellular dsRNA level. Thus, dsRNA editing activities by ADAR1 would in inhibit the activation immune response to the aberrant or chronic innate. In contract, elevated ADAR1-based editing has been found in cancer cells, where ADAR1 would be exploited to elicit hyper-editing so that escape flee immune detection[5]. To this end, three recent studies[6-9] reported that some types of tumor cells can be profoundly sensitized to cancer immunotherapy upon the depletion of ADAR1. In these cancer models, anti-tumour immunity is limited by ADAR1 checkpoint functions through preventing endogenous dsRNA sensing. Whereas loss of function of ADAR1 provokes responses to PD-1 blockade, overcoming the resistance to immunotherapy. In this project we attempted to understand the role of ADAR1 interference in modulating immune response in cancer.

References:

1. Lamers, M.M., B.G. van den Hoogen, and B.L. Haagmans, ADAR1:“Editor-in-Chief” of Cytoplasmic Innate Immunity. Frontiers in immunology, 2019. 10.
2. Rice, G.I., et al., Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nature genetics, 2012. 44(11): p. 1243.
3. Crow, Y.J., et al., Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American journal of medical genetics Part A, 2015. 167(2): p. 296-312.
4. Liddicoat, B.J., et al., RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science, 2015. 349(6252): p. 1115-1120.
5. Fritzell, K., et al. ADARs and editing: the role of A-to-I RNA modification in cancer progression. in Seminars in cell & developmental biology. 2018. Elsevier.
6. Liu, H., et al., Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nature medicine, 2019. 25(1): p. 95-102.
7. Ishizuka, J.J., et al., Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature, 2019. 565(7737): p. 43-48.
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