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Synergistic Activation of Macrophages via CD40 and TLR9 Results in T Cell Independent Antitumor Effects¹

Ilia N. Buhtoiarov^2,*, Hillary D. Lum^*, Gideon Berke, Paul M. Sondel^*, and Alexander L. Rakhmilevich^3,*

^* 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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