Tumor cells infected with oncolytic influenza A virus prime natural killer cells for lysis of resistant tumor cells.
Tumor resistance to lysis by resting natural killer (NK) cells may be overcome by priming of NK cells with cytokines or by binding of NK activating receptors to ligands expressed on target cells. In this study, major histocompatibility complex class I (MHC-I)-negative LNCaP and MHC-I-positive DU145 cells were infected with genetically modified influenza A virus lacking the non-structural gene 1 (NS1 IAV). The cells were used to investigate the influence of NS1 IAV infection on NK cell lysis of tumor cells as well as to prime NK cells for lysis of LNCaP and DU145 cells. While LNCaP cells infected with DeltaNS1 IAV showed enhanced lysis when compared with mock-infected cells (93% +/- 1.47 vs. 52% +/- 0.74), both mock-infected and DeltaNS1 IAV-infected DU145 cells were resistant to NK cell lysis. Moreover, NK cells primed with DeltaNS1 IAV-infected LNCaP/DU145 cells effectively lysed resistant DU145 and sensitive LNCaP cells to a greater extent than NK cells primed with mock-infected LNCaP/DU145 or non-primed NK cells. Also, NK cell priming with DeltaNS1 IAV-infected tumor cells enhanced extracellular signal-regulated kinase phosphorylation and increased granule release in NK cells. The increased granule release was specifically mediated by NKp46, which eventually potentiated NK cells primed with DeltaNS1 IAV-infected tumor cells to overcome the inhibitory effects posed by MHC-I expression on DU145 cells. These findings show that in addition to direct lytic activity of NK cells, DeltaNS1 IAV may influence anti-tumoral responses by priming NK cells.
Ogbomo
Henry
H
Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Michaelis
Martin
M
Geiler
Janina
J
van Rikxoort
Marijke
M
Muster
Thomas
T
Egorov
Andrej
A
Doerr
Hans Wilhelm
HW
Cinatl
Jindrich
J
D019496:Cancer Vaccines; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D002470:Cell Survival; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000276:immunology; D050504:Oncolytic Viruses / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000821:virology
D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D055627:Natural Cytotoxicity Triggering Receptor 1