Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay.
Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay.
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肿瘤不受免疫系统控制的主要原因是，与病原体不同，它们不表达有效的肿瘤排斥抗原（TRAs）。肿瘤疫苗接种的目的是刺激针对弥散性肿瘤病变中表达的大多数弱抗原的全身免疫反应。制定有效疫苗接种方案的主要挑战是确定有效和广泛表达的TRAs和有效的佐剂，以刺激强大和持久的免疫反应。在这里，我们描述了另一种方法，即通过抑制无义介导的信使RNA衰变（NMD），在肿瘤细胞中诱导新的有效抗原的表达。肿瘤细胞中小干扰RNA （siRNA）介导的NMD抑制导致新的抗原决定因子的表达及其免疫介导的排斥反应。在皮下和转移性肿瘤模型中，靶向递送与寡核苷酸适配体配体结合的NMD因子特异性sirna可显著抑制肿瘤生长，其抑制效果优于接种表达粒细胞-巨噬细胞集落刺激因子（GM-CSF）的辐照肿瘤细胞，并可通过共刺激进一步增强。肿瘤靶向NMD抑制是增强播散性肿瘤抗原性的一种简单、广泛、临床可行的方法，可导致其免疫识别和排斥。无细胞化学合成的适配体- sirna的寡核苷酸主链降低了免疫原性的风险，提高了生成适合临床使用的试剂的可行性。
The main reason why tumours are not controlled by the immune system is that, unlike pathogens, they do not express potent tumour rejection antigens (TRAs). Tumour vaccination aims at stimulating a systemic immune response targeted to, mostly weak, antigens expressed in the disseminated tumour lesions. Main challenges in developing effective vaccination protocols are the identification of potent and broadly expressed TRAs and effective adjuvants to stimulate a robust and durable immune response. Here we describe an alternative approach in which the expression of new, and thereby potent, antigens are induced in tumour cells by inhibiting nonsense-mediated messenger RNA decay (NMD). Small interfering RNA (siRNA)-mediated inhibition of NMD in tumour cells led to the expression of new antigenic determinants and their immune-mediated rejection. In subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to significant inhibition of tumour growth that was superior to that of vaccination with granulocyte–macrophage colony-stimulating factor (GM-CSF)-expressing irradiated tumour cells, and could be further enhanced by co-stimulation. Tumour-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumours leading to their immune recognition and rejection. The cell-free chemically synthesized oligonucleotide backbone of aptamer–siRNAs reduces the risk of immunogenicity and enhances the feasibility of generating reagents suitable for clinical use.
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影响因子：
46.9
作者：
Judge, AD;Sood, V;MacLachlan, I
通讯作者：
MacLachlan, I
影响因子：
15.9
作者：
McNamara, James O., II;Kolonias, Despina;Gilboa, Eli
通讯作者：
Gilboa, Eli
影响因子：
30.8
作者：
Mendell, JT;Sharifi, NA;Dietz, HC
通讯作者：
Dietz, HC
DOI：
10.1084/jem.20030590
发表时间：
2003-08-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Overwijk WW;Theoret MR;Finkelstein SE;Surman DR;de Jong LA;Vyth-Dreese FA;Dellemijn TA;Antony PA;Spiess PJ;Palmer DC;Heimann DM;Klebanoff CA;Yu Z;Hwang LN;Feigenbaum L;Kruisbeek AM;Rosenberg SA;Restifo NP
通讯作者：
Restifo NP
DOI：
10.1073/pnas.90.8.3539
发表时间：
1993-04-15
影响因子：
11.1
作者：
DRANOFF, G;JAFFEE, E;MULLIGAN, RC
通讯作者：
MULLIGAN, RC