Tellam Judy, Connolly Geoff, Webb Natasha, Duraiswamy Jaikumar, Khanna Rajiv
Queensland Institute of Medical Research, Bancroft Centre, 300 Herston Rd, Brisbane, Australia 4029.
Blood. 2003 Dec 15;102(13):4535-40. doi: 10.1182/blood-2003-03-0870. Epub 2003 Aug 14.
The ability of viral or mutated cellular oncogenes to initiate neoplastic events and their poor immunogenicity have considerably undermined their potential use as immunotherapeutic tools for the treatment of human cancers. Using an Epstein-Barr virus-encoded oncogene, latent membrane protein 1 (LMP1), as a model, we report a novel strategy that both deactivates cellular signaling pathways associated with the oncogenic phenotype and reverses poor immunogenicity. We show that cotranslational ubiquitination combined with N-end rule targeting of LMP1 enhanced the intracellular degradation of LMP1 and total blockade of LMP1-mediated nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription (STAT) activation in human cells. In addition, although murine cells expressing LMP1 were uniformly tumorigenic, this oncogenicity was completely abrogated by covalent linkage of LMP1 with ubiquitin, while an enhanced CD8+ T cell response to a model epitope fused to the C-terminus of LMP1 was observed following immunization with ubiquitinated LMP1. These observations suggest that proteasomal targeting of tumor-associated oncogenes could be exploited therapeutically by either gene therapy or vaccination.
病毒癌基因或突变细胞癌基因引发肿瘤事件的能力及其较差的免疫原性，极大地削弱了它们作为免疫治疗工具用于治疗人类癌症的潜力。以爱泼斯坦-巴尔病毒编码的癌基因潜伏膜蛋白1（LMP1）为模型，我们报告了一种新策略，该策略既能使与致癌表型相关的细胞信号通路失活，又能逆转较差的免疫原性。我们发现，共翻译泛素化结合LMP1的N端规则靶向增强了LMP1在细胞内的降解，并完全阻断了LMP1介导的人类细胞中核因子κB（NF-κB）和信号转导与转录激活因子（STAT）的激活。此外，虽然表达LMP1的小鼠细胞均具有致瘤性，但LMP1与泛素的共价连接完全消除了这种致癌性，而在用泛素化LMP1免疫后，观察到对与LMP1 C末端融合的模型表位的CD8+T细胞反应增强。这些观察结果表明，通过基因治疗或疫苗接种，可利用蛋白酶体靶向肿瘤相关癌基因进行治疗。
