Abstract LB-369: Coxsackievirus B3 is an immunostimulatory oncolytic virus active against lung adenocarcinoma
| Autor: | Yasuo Urata, Hiroyuki Shimizu, Keisuke Yasunari, Koichi Takayama, Tomotoshi Marumoto, Meiko Yamada, Shohei Miyamoto, Takafumi Nakamura, Kenzaburo Tani, Hiroyuki Inoue, Atsushi Takahashi, Yoichi Nakanishi, Beibei Wang |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Cancer Research. 72:LB-369 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2012-lb-369 |
| Popis: | Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacies are hampered by low tumor selectivity. To identify a potent and selective oncolytic virus, we performed large-scale two-step screening of 28 enteroviral strains and found that coxsackievirus B3 (CVB3) possessed specific oncolytic activity against nine human non-small cell lung cancer (NSCLC) cell lines. CVB3-mediated cytotoxicity was positively correlated with the expression of viral receptors, CAR and DAF, on NSCLC cells, and attenuated by loss of CAR expression by siRNA transfection on NSCLC cells. In vitro assays revealed that CVB3 induced apoptosis and PI3K/Akt and MEK/ERK survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of pre-established tumors in vivo. Furthermore, administration of CVB3 into xenografts on the right flank resulted in significantly durable regression of uninjected xenografts on the left flank, where replication-competent CVB3 was detected. All treatments with CVB3 were well-tolerated without treatment-related deaths. In addition, intratumoral CVB3 administration markedly recruited NK cells and granulocytes, both of which expressed cytolytic degranulation marker CD107a and contributed to the antitumor effects as demonstrated by depletion assays, macrophages, and mature dendritic cells (DCs) into tumor tissues. Furthermore, we found that CVB3 infection induced abundant calreticulin (CRT) exposure, known as a major checkpoint of immunogenic cell death, on the cell surface of NSCLC cells, as well as extranuclear high mobility group box 1 (HMGB1) translocation from the nuclei to the cytosol in NSCLC cells. Altogether, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC and may yield a unique and more effective antitumor activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-369. doi:1538-7445.AM2012-LB-369 |
| Databáze: | OpenAIRE |
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