References
Query Results -- Details
MGI Accession ID: MGI:3760926
J Number: J:126263
Other Accession IDs:
Title: Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects.
Authors: Buhtoiarov IN; Lum HD; Berke G; Sondel PM; Rakhmilevich AL
Journal: J Immunol
Volume: 176
Issue: 1
Date: 2006 Jan 1
Year: 2006
Pages: 309-18
Review Status: Peer Reviewed
Abstract:
We have previously shown that macrophages (Mphi) can be activated by CD40 ligation to become cytotoxic against tumor cells in vitro. Here we show that treatment of mice with agonistic anti-CD40 mAb (anti-CD40) induced up-regulation of intracellular TLR9 in Mphi and primed them to respond to CpG-containing oligodeoxynucleotides (CpG), resulting in synergistic activation. The synergy between anti-CD40 and CpG was evidenced by increased production of IFN-gamma, IL-12, TNF-alpha, and NO by Mphi, as well as by augmented apoptogenic effects of Mphi against tumor cells in vitro. The activation of cytotoxic Mphi after anti-CD40 plus CpG treatment was dependent on IFN-gamma but not TNF-alpha or NO, and did not require T cells and NK cells. Anti-CD40 and CpG also synergized in vivo in retardation of tumor growth in both immunocompetent and immunodeficient mice. Inactivation of Mphi in SCID/beige mice by silica treatment abrogated the antitumor effect. Taken together, our results show that Mphi can be activated via CD40/TLR9 ligation to kill tumor cells in vitro and inhibit tumor growth in vivo even in immunocompromised tumor-bearing hosts, indicating that this Mphi-based immunotherapeutic strategy may be appropriate for clinical testing.
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