PIAS1 and STAT-3 impair the tumoricidal potential of IFN-γ-stimulated mouse dendritic cells generated with IL-15.
Primarily defined by their antigen-presenting property, dendritic cells (DCs) are being implemented as cancer vaccines in immunotherapeutic interventions. DCs can also function as direct tumor cell killers. How DC cytotoxic activity can be efficiently harnessed and the mechanisms controlling this nonconventional property are not fully understood. We report here that the tumoricidal potential of mouse DCs generated from myeloid precursors with GM-CSF and IL-15 (IL-15 DCs) can be triggered with the Toll-like receptor (TLR) 4 ligand lipopolysaccharide to a similar extent compared with that of their counterparts, conventionally generated with IL-4 (IL-4 DCs). The mechanism of tumor cell killing depends on the induction of iNOS expression by DCs. In contrast, interferon (IFN)-γ induces the cytotoxic activity of IL-4 but not IL-15 DCs. Although the IFN-γ-STAT-1 signaling pathway is overall functional in IL-15 DCs, IFN-γ fails to induce iNOS expression in these cells. iNOS expression is negatively controlled in IFN-γ-stimulated IL-15 DCs by the cooperation between the E3 SUMO ligase PIAS1 and STAT-3, and can be partially restored with PIAS1 siRNA and STAT-3 inhibitors.
Department of Pediatrics, University of Arizona, Tucson, AZ, United States of America.|Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United States of America.
Neale T
NT
Hanke
Department of Pediatrics, University of Arizona, Tucson, AZ, United States of America.|Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United States of America.
Collin J
CJ
LaCasse
Department of Pediatrics, University of Arizona, Tucson, AZ, United States of America.
Claire B
CB
Larmonier
Department of Pediatrics, University of Arizona, Tucson, AZ, United States of America.|Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United States of America.
Darya
D
Alizadeh
INSERM UMR 1098, Faculty of Medicine, Dijon, France.
Malika
M
Trad
INSERM UMR 1098, Faculty of Medicine, Dijon, France.
Nona
N
Janikashvili
INSERM UMR 1098, Faculty of Medicine, Dijon, France.
Bernard
B
Bonnotte
Department of Pediatrics, University of Arizona, Tucson, AZ, United States of America.|Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United States of America.|Department of Immunobiology, BIO5 Institute and Arizona Cancer Center, University of Arizona, Tucson, AZ, United States of America.
Emmanuel
E
Katsanis
Department of Pediatrics, University of Arizona, Tucson, AZ, United States of America.|Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United States of America.|Department of Immunobiology, BIO5 Institute and Arizona Cancer Center, University of Arizona, Tucson, AZ, United States of America.
Nicolas
N
Larmonier
D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D019409:Interleukin-15 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D019409:Interleukin-15; D008024:Ligands; D008070:Lipopolysaccharides; C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
Cytotoxic dendritic cells; NF-κB; PIAS1; STAT-3; iNOS