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[Cancer Research 62, 4406-4412, August 1, 2002]
© 2002 American Association for Cancer Research

Immunology

Interferon-{gamma}-dependent Phagocytic Cells Are a Critical Component of Innate Immunity against Metastatic Mammary Carcinoma1

Beth A. Pulaski, Mark J. Smyth and Suzanne Ostrand-Rosenberg2

Department of Biological Sciences, University of Maryland-Baltimore County, Baltimore, Maryland 21250 [B. A. P, S. O-R.], and Cancer Immunology Program and Peter MacCallum Cancer Institute, East Melbourne, Victoria 8006, Australia [M. J. S.]

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.




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