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Published online before print March 24, 2006

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(Journal of Leukocyte Biology. 2006;79:1181-1192.)
© 2006 by Society for Leukocyte Biology

In vivo CD40 ligation can induce T cell-independent antitumor effects that involve macrophages

Hillary D. Lum^*, Ilia N. Buhtoiarov^*, Brian E. Schmidt^*, Gideon Berke, Donna M. Paulnock, Paul M. Sondel^*,,¶ and Alexander L. Rakhmilevich^*,,1

^* Departments of Human Oncology,
Medical Microbiology and Immunology, and
^¶ Pediatrics and
Comprehensive Cancer Center, University of Wisconsin, Madison; and
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

¹Correspondence: University of Wisconsin-Madison, K4/413 Clinical Science Center, Department of Human Oncology, 600 Highland Avenue, Madison, WI 53792. E-mail: rakhmil{at}humonc.wisc.edu

ABSTRACT

We have previously demonstrated T cell-independent antitumor and antimetastatic effects of CD40 ligation that involved natural killer (NK) cells. As CD40 molecules are expressed on the surface of macrophages (M), we hypothesized that M may also serve as antitumor effector cells when activated by CD40 ligation. Progression of subcutaneous NXS2 murine neuroblastomas was delayed significantly by agonistic CD40 monoclonal antibody (anti-CD40 mAb) therapy in immunocompetent A/J mice, as well as in T and B cell-deficient severe combined immunodeficiency (SCID) mice. Although NK cells can be activated by anti-CD40 mAb, anti-CD40 mAb treatment also induced a significant antitumor effect in SCID/beige mice in the absence of T and NK effector cells, even when noncytolytic NK cells and polymorphonuclear cells (PMN) were depleted. Furthermore, in vivo treatment with anti-CD40 mAb resulted in enhanced expression of cytokines and cell surface activation markers, as well as M-mediated tumor inhibition in A/J mice, C57BL/6 mice, and SCID/beige mice, as measured in vitro. A role for M was shown by reduction in the antitumor effect of anti-CD40 mAb when M functions were inhibited in vivo by silica. In addition, activation of peritoneal M by anti-CD40 mAb resulted in survival benefits in mice bearing intraperitoneal tumors. Taken together, our results show that anti-CD40 mAb immunotherapy of mice can inhibit tumor growth in the absence of T cells, NK cells, and PMN through the involvement of activated M.

Key Words: antitumor • anti-CD40 mAb • tumor immunotherapy

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