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* Department of Human Oncology and Comprehensive Cancer Center and
Department of Pediatrics, University of Wisconsin, Madison, WI 53792; and
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
We have previously shown that macrophages (M
) 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 M 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-
, IL-12, TNF-
, and NO by M, as well as by augmented apoptogenic effects of M against tumor cells in vitro. The activation of cytotoxic M after anti-CD40 plus CpG treatment was dependent on IFN- but not TNF- 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 M in SCID/beige mice by silica treatment abrogated the antitumor effect. Taken together, our results show that M 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 M-based immunotherapeutic strategy may be appropriate for clinical testing.
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