title: Tumor-specific bacteriophages induce tumor destruction through activation of tumor-associated macrophages.
abstract: 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.
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska R8:01, Immune and Gene Therapy Laboratory, Karolinska Institute, Stockholm, Sweden. fredrik.eriksson@ki.se
authors.forename: Fredrik
authors.initials: F
authors.lastname: Eriksson
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Tsagozis
authors.forename: Kajsa
authors.initials: K
authors.lastname: Lundberg
authors.forename: Roham
authors.initials: R
authors.lastname: Parsa
authors.forename: Sara M
authors.initials: SM
authors.lastname: Mangsbo
authors.forename: Mats A A
authors.initials: MA
authors.lastname: Persson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Pavel
authors.initials: P
authors.lastname: Pisa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D017104:Bacteriophage M13 / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors