title: Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma.
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 decay-accelerating 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.
authors.affiliation: Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Meiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Chika
authors.initials: C
authors.lastname: Sakamoto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Urata
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Okazaki
authors.forename: Tomotoshi
authors.initials: T
authors.lastname: Marumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Takayama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Kenzaburo
authors.initials: K
authors.lastname: Tani
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D029822:Enterovirus B, Human; D005260:Female; D006801:Humans; D007114:Immunization; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses