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* Department of Oncology and Pathology, Cancer Center Karolinska R8:01, Immune and Gene Therapy Laboratory, Karolinska Institute, Stockholm, Sweden;
Department of Clinical Neuroscience, Centre for Molecular Medicine L8:04, Karolinska University Hospital, Stockholm, Sweden;
Department of Oncology, Radiology and Clinical Immunology, Division of Clinical Immunology, Rudbeck Laboratory C11, Uppsala University, Uppsala, Sweden; and
Department of Medicine, Centre for Molecular Medicine L8:01, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
We recently reported that administration of tumor-specific bacteriophages initiates infiltration of neutrophilic granulocytes with subsequent regression of established B16 tumors. The aim of the current study was to investigate the mechanism of action of bacteriophage-induced tumor regression and to examine possible stimulatory effects of bacteriophages on macrophages. We observed that the mechanism of phage-induced tumor regression is TLR dependent as no signs of tumor destruction or neutrophil infiltration were observed in tumors in MyD88–/– mice in which TLR signaling is abolished. The microenvironment of bacteriophage-treated tumors was further analyzed by gene profiling through applying a low-density array preferentially designed to detect genes expressed by activated APCs, which demonstrated that the M2-polarized tumor microenvironment switched to a more M1-polarized milieu following phage treatment. Bacteriophage stimulation induced secretion of proinflammatory cytokines in both normal mouse macrophages and tumor-associated macrophages (TAMs) and increased expression of molecules involved in Ag presentation and costimulation. Furthermore, mouse neutrophils selectively migrated toward mediators secreted by bacteriophage-stimulated TAMs. Under these conditions, the neutrophils also exhibited increased cytotoxicity toward B16 mouse melanoma target cells. These results describe a close interplay of the innate immune system in which bacteriophages, located to the tumor microenvironment due to their specificity, stimulate TAMs to secrete factors that promote recruitment of neutrophils and potentiate neutrophil-mediated tumor destruction.
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 work was supported partly by grants from the Cancer Society in Stockholm, the Swedish Cancer Society, Karolinska Institute Funds, the Swedish Research Council (Medical Branch), the EU 6-FP "ALLOSTEM" (LSHB-CT-2004-503319), the EU 6-FP "ENACT", and U.S. Department of Defense Prostate Cancer Research Program (PC030958).
2 Address correspondence and reprint requests to Dr. Fredrik Eriksson, Cancer Center Karolinska (CCK), R8:01, Karolinska University Hospital SE-171 76 Stockholm, Sweden. E-mail address: fredrik.eriksson{at}ki.se
3 P.T. and K.L. contributed equally to this manuscript.
4 Abbreviations used in this paper: TAM, tumor-associated macrophage; LDA, low-density array; CM, complete medium.
5 The online version of this article contains supplementary material.
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