ADAR and Immune Silencing in Cancer

RNA editing by ADAR is a pan-cancer process that a significant fraction of tumors rely on for survival. It promotes immune silencing and tumor viability. Reducing ADAR expression in tumors increases sensitivity to checkpoint inhibitors in mouse melanoma models. IFN, along with Alu dsRNA and cytoplasmic DNA, trigger expression of the p150 isoform of ADAR that enables tumor progression. Mendelian diseases validate the Z-DNA/Z-RNA-binding Zα domain of ADAR p150 as a target with a favorable therapeutic index. The Alu editing index is a promising biomarker for patient selection, the scoring of treatment responses, and the prediction of overall response rates and survival. The regulation of immune responses by tumors is central to their survival. By diminishing the production of interferon (IFN) and other inflammatory mediators, tumors enhance immune evasion. Responses initiated by nucleic acid sensors and triggered by dysregulated RNA transcription and cytoplasmic DNA undergo down-modulation in tumors. A protein hub that involves the double-stranded RNA (dsRNA) editing enzyme adenosine deaminase RNA specific (ADAR), the RNase DICER1, and the dsRNA-activated kinase protein activator of PKR (PACT) mediates many of these tumor-intrinsic responses, with in vitro ADAR dependency varying by tumor type (range 11–80%). The central role played by ADAR, both as an enzyme and as a scaffold, sets it as a target for cancer immunotherapy. Therapeutic approaches focusing on the ADAR p150 isoform and its Z-DNA- and Z-RNA-specific Zα domain find support from recent mouse and human studies. The regulation of immune responses by tumors is central to their survival. By diminishing the production of interferon (IFN) and other inflammatory mediators, tumors enhance immune evasion. Responses initiated by nucleic acid sensors and triggered by dysregulated RNA transcription and cytoplasmic DNA undergo down-modulation in tumors. A protein hub that involves the double-stranded RNA (dsRNA) editing enzyme adenosine deaminase RNA specific (ADAR), the RNase DICER1, and the dsRNA-activated kinase protein activator of PKR (PACT) mediates many of these tumor-intrinsic responses, with in vitro ADAR dependency varying by tumor type (range 11–80%). The central role played by ADAR, both as an enzyme and as a scaffold, sets it as a target for cancer immunotherapy. Therapeutic approaches focusing on the ADAR p150 isoform and its Z-DNA- and Z-RNA-specific Zα domain find support from recent mouse and human studies. a type I interferonopathy that varies in age of onset and severity. a repetitive element derived from the 7SL RNA of the signal recognition particle (SRP). Alus comprise ∼5% of the human genome. The dimeric form of this repeat is ∼280 bp. It is named after the restriction enzyme that first reveled its presence in genomic DNA. a normalized measure based on hyperediting of Alu elements that allows comparison of editing activity across tissues and tumors. a severe type 1 interferonopathy associated with cerebral calcifications. an autosomal-dominant disease produced by ADAR haploinsufficiency and characterized by hypo- and hyperpigmented macules on the face and the dorsal surfaces of the hands and feet. dsRNA produced by genomic transcription; most commonly, Alu IREs. tumors downregulate pathways triggered by damage sensors such as those that respond to cytoplasmic DNA or the accumulation of dsRNA. These aberrant cells do not produce any type of alarm to trigger their elimination. The immune system stays ignorant of their presence. through a process of selection, tumors emerge that no longer express surface antigens capable of activating the adaptive immune system. These edited tumors escape elimination by T cells. the sets of genes expressed in response to type I, type II, and type III IFNs [84Schneider W.M. et al.Interferon-stimulated genes: a complex web of host defenses.Annu. Rev. Immunol. 2014; 32: 513-545Crossref PubMed Scopus (1748) Google Scholar]. formed when two copies of the same or almost identical DNA sequence are in close proximity to one another with one encoded in the reverse orientation to the other. In the Homo sapiens genome, IREs are due mostly to Alu repeat elements. Following transcription, IREs fold back on themselves and base pair, forming regions of dsRNA. each conformation of dsDNA energetically favors a certain number of base pairs per helical turn. When both ends of the helix are fixed in place, twisting of one end in a direction that forces the double helix to have fewer base pairs per turn than ideal produces NSS. In the case of B-DNA, changing one segment of the helix from a right-handed spiral to a left-handed Z-DNA spiral relieves NSS. The B-DNA segment and the Z-DNA segment each adopt their preferred helical parameters. NSS arises physiologically inside cells through the action of processive enzymes, such as polymerases, that track along the double helix unwinding it as they proceed. protein residues that direct its export from the nucleus to the cytoplasm. protein residues that direct its import into the nucleus from the cytoplasm. involved in the RNAi of gene expression. processed by the RISC to negatively regulate mRNA expression through base-specific interactions, either decreasing RNA stability or inhibiting its translation. stalls protein translation until the ribosome docks with the endoplasmic reticulum (ER). Protein translation then restarts and the product translocates through the membrane into the lumen of the ER. a noncoding RNA that regulates the expression by genes through interactions with steroid nuclear receptors. a domain of ADAR that was the first protein known to bind specifically to left-handed dsDNA and dsRNA conformations with high affinity. Related domains exist in a number of viral proteins. a domain present in ADAR related to Zα that lacks a key tyrosine essential for high-affinity Z-DNA binding. Its function is unknown. Related Zβ domains in other proteins bind Z-DNA in a slightly different way than Zα does.