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PolyI:C-Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector-Mediated Tumor Elimination In Vivo

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タイトル: PolyI:C-Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector-Mediated Tumor Elimination In Vivo
その他のタイトル: TICAM-1-RIP3 necroptosis in tumor
著者: Takemura, Ryo 著作を一覧する
Takaki, Hiromi 著作を一覧する
Okada, Seiji 著作を一覧する
Shime, Hiroaki 著作を一覧する
Akazawa, Takashi 著作を一覧する
Oshiumi, Hiroyuki 著作を一覧する
Matsumoto, Misako 著作を一覧する
Teshima, Takanori 著作を一覧する
Seya, Tsukasa 著作を一覧する
キーワード: RNA (polyI:C)
RIP kinases
発行日: 2015年 8月
出版者: American Association for Cancer Research
誌名: Cancer immunology research
巻: 3
号: 8
開始ページ: 902
終了ページ: 914
出版社 DOI: 10.1158/2326-6066.CIR-14-0219
抄録: Double-stranded RNA directly acts on fibroblast and myeloid lineages to induce necroptosis as in TNFα. Here, we investigated whether this type of cell death occurred in cancer cells in response to polyinosinic-polycytidylic acid (polyI:C) and the pan-caspase inhibitor z-Val-Ala-Asp fluromethyl ketone (zVAD). We found that the colon cancer cell line CT26 is highly susceptible to necroptosis, as revealed by staining with annexin V/propidium iodide. CT26 cells possess RNA sensors, TLR3 and MDA5, which are upregulated by interferon (IFN)-inducing pathways and linked to receptor-interacting protein kinase (RIP) 1/3 activation via TICAM-1 or MAVS adaptor, respectively. Although exogenously added polyI:C alone marginally induced necroptosis in CT26 cells, a combined regimen of polyI:C and zVAD induced approximately 50% CT26 necroptosis in vitro without secondary effects of TNFα or type I IFNs. CT26 necroptosis depended on the TLR3-TICAM-1-RIP3 axis in the tumor cells to produce reactive oxygen species, but not on MDA5, MAVS, or the caspases/inflammasome activation. However, the RNA-derived necroptosis was barely reproduced in vivo in a CT26 tumor-implanted Balb/c mouse model with administration of polyI:C + zVAD. Significant shrinkage of CT26 tumors was revealed only when polyI:C (100 μg) was injected intraperitoneally and zVAD (1 mg) subcutaneously into tumor-bearing mice that were depleted of cytotoxic T lymphocytes and natural killer cells. The results were confirmed with immune-compromised mice with no lymphocytes. Although necroptosis-induced tumor growth retardation appears mechanistically complicated and dependent on the injection routes of polyI:C and zVAD, anti-caspase reagent directed to tumor cells will make RNA adjuvant immunotherapy more effective by modulating the formation of the tumoricidal microenvironment and dendritic cell-inducing antitumor immune system.
資料タイプ: article (author version)
出現コレクション:雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

提供者: 瀬谷 司


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