Tumor immunotherapy by plasmid DNAs encoding adenovirus virus-associated RNA†

Tomoko Ito, Takayuki Yoshimoto, Izuru Mizoguchi and Yoshiyuki Koyama
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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.

Abstract Image

编码腺病毒相关RNA†的质粒dna对肿瘤的免疫治疗
免疫疗法已经成为一种最有前途的癌症治疗武器;然而,肿瘤抗原通常表现出低免疫原性,限制了其有效性。相反,病毒感染有效地触发先天和适应性免疫。这归因于微生物抗原的高免疫原性和模式识别受体的激活,如视黄酸诱导基因i (RIG-I)。在识别病毒RNA后,rig - 1诱导分泌i型干扰素(ifn)。I型干扰素不仅具有抗病毒作用,而且在肿瘤免疫治疗中发挥着有效的作用。因此,通过配体激活rig - 1作为一种新的癌症免疫治疗方法近年来受到关注。病毒相关rna (VA-RNA I和VA-RNA II)是由腺病毒基因组产生的非编码小rna。VA-RNA I强烈激活RIG-I,导致I型IFN的产生。本研究制备了同时编码VA-RNA I和II [pDNA(I,II)]或仅编码VA-RNA I [pDNA(I)]的质粒dna,研究其诱导IFN和抗肿瘤作用。在培养细胞中,引入pDNA(I,II)或pDNA(I)可有效诱导IFN-α和IFN-β的产生。两种质粒均显著抑制小鼠肿瘤生长。与pDNA(I,II)相比,pDNA(I)具有更好的诱导ifn和抗肿瘤作用。VA-RNA I基因给药有望成为一种新的抗肿瘤免疫治疗策略。
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