Immunostimulatory RNA oligonucleotides induce an effective antitumoral NK cell response through the TLR7.
RNA oligonucleotides containing immune-activating sequences promote the development of cytotoxic T cell and B cell responses to Ag. In this study, we show for the first time that immunostimulatory RNA oligonucleotides induce a NK cell response that prevents growth of NK-sensitive tumors. Treatment of mice with immunostimulatory RNA oligonucleotides activates NK cells in a sequence-dependent manner, leading to enhanced IFN-gamma production and increased cytotoxicity. Use of gene-deficient mice showed that NK activation is entirely TLR7-dependent. We further demonstrate that NK activation is indirectly induced through IL-12 and type I IFN production by dendritic cells. Reconstitution of TLR7-deficient mice with wild-type dendritic cells restores NK activation upon treatment with immunostimulatory RNA oligonucleotides. Thus, by activating both NK cells and CTLs, RNA oligonucleotides stimulate two major cellular effectors of antitumor immunity. This dual activation may enhance the efficacy of immunotherapeutic strategies against cancer by preventing the development of tumor immune escape variants.
Bourquin
Carole
C
Center for Integrated Protein Science Munich, Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University of Munich, Munich, Germany. carole.bourquin@med.lmu.de
Schmidt
Laura
L
Lanz
Anna-Lisa
AL
Storch
Bettina
B
Wurzenberger
Cornelia
C
Anz
David
D
Sandholzer
Nadja
N
Mocikat
Ralph
R
Berger
Michael
M
Poeck
Hendrik
H
Hartmann
Gunther
G
Hornung
Veit
V
Endres
Stefan
S
D000276:Adjuvants, Immunologic; D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D009843:Oligoribonucleotides / Q000276:immunology* / Q000494:pharmacology; D011061:Poly A / Q000276:immunology / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D007370:Interferon Type I; D009838:Oligodeoxyribonucleotides; D009843:Oligoribonucleotides; D051199:Toll-Like Receptor 7; D011061:Poly A; D007371:Interferon-gamma