Fludarabine as an Adjuvant Improves Newcastle Disease Virus-Mediated Antitumor Immunity in Hepatocellular Carcinoma
Fludarabine as an Adjuvant Improves Newcastle Disease Virus-Mediated Antitumor Immunity in Hepatocellular Carcinoma
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氟达拉滨作为佐剂可改善肝细胞癌中新城疫病毒介导的抗肿瘤免疫
DOI：
10.1016/j.omto.2019.03.004
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发表时间：
2019
影响因子：
5.7
通讯作者：
Wei Jiwu
中科院分区：
文献类型：
--
作者：
Meng Gang;Fei Ziwei;Fang Mingyue;Li Binghua;Chen Anxian;Xu Chun;Xia Mao;Yu Decai;Wei Jiwu
除直接溶瘤外，溶瘤病毒（OVs）还可诱导抗肿瘤免疫，也称为病毒免疫治疗。有限的病毒复制和免疫负反馈是有效的病毒免疫治疗的主要障碍。在这项研究中，我们发现使用氟达拉滨（一种用于慢性髓系白血病的化疗药物）作为佐剂，通过靶向信号换能器和转录激活因子1 （STAT1）来增加新城疫病病毒（NDV）的复制，从而增强肝细胞癌（HCC）细胞的溶瘤作用。此外，氟达拉滨通过增强泛素化而不是蛋白酶体活性来加速泛素-蛋白酶体的降解。这导致磷酸化STAT3和吲哚胺2,3 -双加氧酶1 （IDO1）的降解加速，其表达是由NDV感染诱导的。此外，氟达拉滨显著增加ndv诱导的NK细胞浸润，降低肿瘤微环境中ndv诱导的髓源性抑制细胞（MDSCs）的数量。氟达拉滨的上述作用可显著提高ndv介导的抗肿瘤免疫，延长小鼠肝癌模型的生存期。我们的研究结果表明氟达拉滨可作为溶瘤抗癌病毒免疫治疗的辅助药物。
In addition to direct oncolysis, oncolytic viruses (OVs) also induce antitumor immunity, also called viro-immunotherapy. Limited viral replication and immune-negative feedback are the major hurdles to effective viro-immunotherapy. In this study, we found that use of an adjuvant of fludarabine, a chemotherapeutic drug for chronic myeloid leukemia, increased the replication of Newcastle disease virus (NDV) by targeting signal transducer and activator of transcription 1 (STAT1), which led to enhanced oncolysis of hepatocellular carcinoma (HCC) cells. Moreover, fludarabine accelerated ubiquitin-proteasomal degradation by enhancing ubiquitylation rather than proteasomal activity. This resulted in accelerated degradation of phosphorylated STAT3 and indoleamine 2, 3-dioxygenase 1 (IDO1), whose expression was induced by NDV infection. In addition, fludarabine significantly increased the NDV-induced infiltration of NK cells and decreased the number of NDV-induced myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. The aforementioned effects of fludarabine significantly improved NDV-mediated antitumor immunity and prolonged survival in mouse model of HCC. Our findings indicate the utility of fludarabine as an adjuvant for oncolytic anticancer viro-immunotherapy.