Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma

Shohei Miyamoto, Hiroyuki Inoue, Takafumi Nakamura, Meiko Yamada, Chika Sakamoto, Yasuo Urata, Toshihiko Okazaki, Tomotoshi Marumoto, Atsushi Takahashi, Koichi Takayama, Yoichi Nakanishi, Hiroyuki Shimizu, Kenzaburo Tani

Research output: Contribution to journalArticlepeer-review

108 Citations (Scopus)

Abstract

Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacy is hampered by low tumor selectivity. To identify a potent and selective oncolytic virotherapy, we carried out 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 the viral receptors, coxsackievirus and adenovirus receptor, and decayaccelerating factor, on NSCLC cells. In vitro assays revealed that the CVB3 induced apoptosis and phosphoinositide 3-kinase/Akt and mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of preestablished NSCLC tumors in vivo. Furthermore, administrations 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, after CVB3 infection, NSCLC cells expressed abundant cell surface calreticulin and secreted ATP as well as translocated extranuclear high-mobility group box 1, which are required for immunogenic cell death. Moreover, intratumoral CVB3 administration markedly recruited natural killer cells and granulocytes, both of which contributed to the antitumor effects as shown by depletion assays, macrophages, and mature dendritic cells into tumor tissues. Together, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC.

Original languageEnglish
Pages (from-to)2609-2621
Number of pages13
JournalCancer Research
Volume72
Issue number10
DOIs
Publication statusPublished - May 15 2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma'. Together they form a unique fingerprint.

Cite this