Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation.
Dendritic cells (DCs) are the most potent antigen-presenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell-to-cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP-301 (Telomelysin) is a telomerase-specific replication-competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP-301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-gamma (IFN-gamma) and interleukin 12 (IL-12). Subsequently, IFN-gamma release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T-lymphocytes. Our data suggest that virus-mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.
Endo
Y
Y
Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Sakai
R
R
Ouchi
M
M
Onimatsu
H
H
Hioki
M
M
Kagawa
S
S
Uno
F
F
Watanabe
Y
Y
Urata
Y
Y
Tanaka
N
N
Fujiwara
T
T
D000256:Adenoviridae / Q000276:immunology / Q000502:physiology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology; D050130:Oncolytic Virotherapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology*; D015854:Up-Regulation; D014527:Uric Acid / Q000378:metabolism
D014527:Uric Acid; D046988:Proteasome Endopeptidase Complex