期刊
MOLECULAR THERAPY
卷 26, 期 1, 页码 56-69出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2017.10.014
关键词
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资金
- Canadian Institute for Health Research (CIHR) New Investigator Award - Infection and Immunity [INI-147824]
- Canadian Cancer Society - Lotte & John Hecht Memorial Foundation [703014]
- BioCanRx summer studentship award
- CIHR master's award
- Queen Elizabeth II Graduate Scholarship in Science Technology
- Terry Fox Research Institute [TFF 122868]
- CIHR doctoral fellowship
Oncolytic viruses (OV) are an emerging class of anticancer bio-therapeutics that induce antitumor immunity through selective replication in tumor cells. However, the efficacy of OVs as single agents remains limited. We introduce a strategy that boosts the therapeutic efficacy of OVs by combining their activity with immuno-modulating, small molecule protein tyrosine phosphatase inhibitors. We report that vanadium-based phosphatase inhibitors enhance OV infection in vitro and ex vivo, in resistant tumor cell lines. Furthermore, vanadium compounds increase antitumor efficacy in combination with OV in several syngeneic tumor models, leading to systemic and durable responses, even in models otherwise refractory to OV and drug alone. Mechanistically, this involves subverting the antiviral type I IFN response toward a death-inducing and pro-inflammatory type II IFN response, leading to improved OV spread, increased bystander killing of cancer cells, and enhanced antitumor immune stimulation. Overall, we showcase a new ability of vanadium compounds to simultaneously maximize viral oncolysis and systemic anticancer immunity, offering new avenues for the development of improved immunotherapy strategies.
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