| First Author | Buhtoiarov IN | Year | 2006 |
| Journal | J Immunol | Volume | 176 |
| Issue | 1 | Pages | 309-18 |
| PubMed ID | 16365423 | Mgi Jnum | J:126263 |
| Mgi Id | MGI:3760926 | Doi | 10.4049/jimmunol.176.1.309 |
| Citation | Buhtoiarov IN, et al. (2006) Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects. J Immunol 176(1):309-18 |
| abstractText | 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. |
