title: Interferon-gamma-dependent phagocytic cells are a critical component of innate immunity against metastatic mammary carcinoma.
abstract: IFN-gamma is a pleiotropic cytokine that plays an important role in regulating the growth of primary tumors. Although numerous studies of the effects of IFN-gamma on primary-solid-tumor growth have been performed and several potential mechanisms for its efficacy have been proposed, it remains unclear how IFN-gamma modulates tumor progression and whether it exerts its effects indirectly via host cells or directly by interacting with tumor cells. Using the well-characterized mouse metastatic mammary carcinoma 4T1 in a postsurgery setting, IFN-gamma-deficient mice were found to have significantly shorter survival time relative to wild-type mice, demonstrating that IFN-gamma is also a critical component in regulating innate immunity to metastatic disease. Experiments quantifying lung and liver metastasis indicate that decreased survival of IFN-gamma-deficient mice is attributable to increased metastatic disease. To determine whether IFN-gamma is acting directly on the tumor cells, IFN-gamma-nonresponsive 4T1 cells were generated by transfection (4t1/IRt). Metastasis experiments with 4T1/IRt demonstrated that IFN-gamma mediates its effects via host-derived cells, rather than by directly affecting tumor growth. To identify the population of cells responsible for IFN-gamma efficacy, perforin-deficient, T-cell subset-depleted, natural killer cell-depleted, or carrageenan-treated phagocytic cell-depleted mice were inoculated with 4T1 and assessed for primary tumor growth and metastatic disease. None of the conditions altered primary tumor growth; however, the carrageenan treatment significantly increased metastatic disease in the liver and lungs. Survival experiments in 4T1-inoculated, carrageenan-treated mice confirmed that the elimination of phagocytic cells significantly reduces survival time and yields a survival phenotype comparable with IFN-gamma deficiency. Therefore, IFN-gamma is a critical component of innate immunity to metastatic mammary carcinoma that probably mediates its effects via host-derived phagocytic cells.
authors.affiliation: Department of Biological Sciences, University of Maryland-Baltimore County, Baltimore, Maryland 21250, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Pulaski
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ostrand-Rosenberg
mesh_terms: D000818:Animals; D002455:Cell Division / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000556:secondary; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D054353:Perforin; D010586:Phagocytes / Q000276:immunology*; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma