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* Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292; and
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40292
Tumor-associated macrophages (TAMs) play a major role in promoting tumor growth and metastasis and in suppressing the antitumor immune response. Despite the immunosuppressive environment created by the tumor and enforced by tumor-associated macrophages, treatment of tumor-bearing mice with IL-12 induces tumor regression associated with appearance of activated NK cells and activated tumor-specific CTLs. We therefore tested the hypothesis that IL-12 treatment could alter the function of these tumor-associated suppressor macrophages. Analysis of tumor-infiltrating macrophages and distal TAMs revealed that IL-12, both in vivo and in vitro, induced a rapid (<90 min) reduction of tumor supportive macrophage activities (IL-10, MCP-1, migration inhibitory factor, and TGF
production) and a concomitant increase in proinflammatory and proimmunogenic activities (TNF-
, IL-15, and IL-18 production). Similar shifts in functional phenotype were induced by IL-12 in tumor-infiltrating macrophages isolated from the primary tumor mass and in TAMs isolated from lung containing metastases, spleen, and peritoneal cavity. Therefore, although TAMs display a strongly polarized immunosuppressive functional profile, they retain the ability to change their functional profile to proinflammatory activities given the appropriate stimulus. The ability of IL-12 to initiate this functional conversion may contribute to early amplification of the subsequent destructive antitumor immune response.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by National Institutes of Health Grant CA100656 (to N.K.E.), the Commonwealth of Kentucky Lung Cancer Research Program (to R.D.S.), the American Lung Association of Kentucky (to S.K.W.), and the Commonwealth of Kentucky Research Challenge Trust Fund (to N.K.E., J.S., and R.D.S.).
2 Address correspondence and reprint requests to Dr. Robert D. Stout, Department of Microbiology and Immunology, University of Louisville, School of Medicine, 319 Abraham Flexner Way, Louisville, KY 40292. E-mail address: bobstout{at}louisville.edu
3 Abbreviations used in this paper: TIM, tumor-infiltrating macrophage; TAM, tumor-associated macrophage; MIF, migration inhibitory factor; CBA, cytokine bead array.
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