TLR7 agonist 852A inhibition of tumor cell proliferation is dependent on plasmacytoid dendritic cells and type I IFN.
Antitumor effects of the toll-like receptor 7 (TLR7) agonist, 852A, were evaluated. Supernatants from human peripheral blood mononuclear cells (PBMC) stimulated with 852A inhibited the proliferation of tumor cell lines Hs294T and 769-P but had no effect on others (786-O and Caki-1). Because addition of 852A directly to the Hs294T cells did not inhibit their proliferation, the mechanism(s) of inhibition of tumor cell proliferation was investigated. Low nanomolar concentrations of 852A stimulated the production of interferon-alpha (IFN-alpha), IFN-inducible protein-10 (IP-10), interleukin-1 receptor antagonist (IL-1Ra), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from human PBMCs. Cytokines stimulated by submicromolar concentrations of 852A were sufficient to inhibit Hs294T proliferation. At higher concentrations (3-30 microM), 852A induced the production of IL-12p70, IL-18, and IFN-gamma. PBMC cultures depleted of plasmacytoid dendritic cells (pDC) did not produce IFN-alpha, and their conditioned medium did not inhibit Hs294T proliferation. Anti-IFN-alpha/beta receptor (IFNAR) and anti-IFN-alpha antibodies partially abrogated Hs294T proliferation inhibition by 852A-stimulated PBMC supernatants, whereas separate neutralization of TRAIL, tumor necrosis factor-alpha (TNF-alpha, IFN-gamma, IFN-beta, or IFN-omega had no effect. In vivo, six doses of 852A administration significantly delayed the onset of lung colonies in a B16 melanoma model. Thus, the results demonstrate that the TLR7 agonist 852A inhibits in vitro proliferation of some tumor cells in a pDC-dependent and IFN-alpha-dependent manner and can delay tumor growth in vivo.
Inglefield
Jon R
JR
3M Company, St Paul, MN 55144, USA.
Dumitru
Calin Dan
CD
Alkan
Sefik S
SS
Gibson
Sheila J
SJ
Lipson
Kenneth E
KE
Tomai
Mark A
MA
Larson
Chris J
CJ
Vasilakos
John P
JP
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D000077271:Imiquimod; D007370:Interferon Type I / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008545:Melanoma / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000473:pathology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051217:Toll-Like Receptor 9 / Q000819:agonists
D000634:Aminoquinolines; C526902:CpG ODN 2216; D017077:Culture Media, Conditioned; D007370:Interferon Type I; C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D009838:Oligodeoxyribonucleotides; D011804:Quinolines; D013449:Sulfonamides; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D000077271:Imiquimod