Journal
MOLECULAR THERAPY-ONCOLYTICS
Volume 13, Issue -, Pages 22-34Publisher
CELL PRESS
DOI: 10.1016/j.omto.2019.03.004
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Funding
- National Natural Science Foundation of China [81773255, 81602702, 81472820, 81871967]
- Natural Science Foundation of Jiangsu Province of China [20160126]
- Social Development Foundation of Jiangsu Province of China [BE2018604]
- China Postdoctoral Science Foundation [2018M642223]
- Six Talent Peaks Project in Jiangsu Province
- Jiangsu Provincial Medical Talent
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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.
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