Tumor immunotherapy by plasmid DNAs encoding adenovirus virus-associated RNA

Abstract

Immunotherapy has become a most promising weapon for cancer treatment; however, tumor antigens generally exhibit low immunogenicity, limiting its effectiveness. In contrast, viral infections efficiently trigger innate and adaptive immunity. This is attributed to the high immunogenicity of microbial antigens and also to the activation of pattern recognition receptors such as retinoic acid-inducible gene-I (RIG-I). Upon recognizing viral RNA, RIG-I induces secretion of type-I interferons (IFNs). Type I IFNs not only invite antiviral effects but also plays an effective role in cancer immunotherapy. Therefore, activation of RIG-I by the ligands has gained attention as a novel cancer immunotherapy in recent years. Virus-associated RNAs (VA-RNA I and VA-RNA II) are non-coding small RNAs generated from the adenovirus genome. VA-RNA I strongly activates RIG-I, leading to type-I IFN production. In this study, plasmid DNAs encoding both VA-RNA I and II [pDNA(I,II)] or only VA-RNA I [pDNA(I)] were prepared, and their IFN inducing and anti-tumor effects were investigated. In culture cells, introduction of pDNA(I,II) or pDNA(I) effectively induced both IFN-α and IFN-β production. Both plasmids significantly inhibited tumor growth in mice. pDNA(I) exhibited superior IFN-inducing and anti-tumor effects compared to pDNA(I,II). VA-RNA I gene administration holds promise as a novel anti-tumor immunotherapy strategy.