Interferon-gamma-dependent phagocytic cells are a critical component of innate immunity against metastatic mammary carcinoma.

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.

Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease.

Immunotherapy is a promising approach for the management of malignancies. It may be particularly useful for tumors that do not respond to conventional therapies, such as many metastatic cancers. The efficacy of immunotherapy will depend on many factors, one of which is the immunocompetence of the host. Patients with large primary tumors frequently are immunosuppressed, making them poor candidates for immunotherapy. Although a few studies have reported that surgical removal of primary tumor reverses immunosuppression, it is not known whether metastatic disease in postsurgery patients inhibits this recovery. To determine the role of metastatic disease, we examined tumor-free mice versus mice with primary tumor and metastatic disease versus mice whose primary tumors were removed surgically but who had metastatic disease. We have used the mouse 4T1 mammary carcinoma, a BALB/c-derived transplantable tumor that shares many characteristics with human breast cancer and is an established model for spontaneous, metastatic cancer. Cell-mediated and humoral adaptive immunity, as measured by rejection of allogeneic tumor, antigen-specific T-cell proliferation, and antigen-specific antibody responses, was suppressed in 4T1-bearing nonsurgery mice relative to tumor-free mice. Surgical removal of primary tumor resulted in rebounding of antibody and cell-mediated responses, even in mice with metastatic disease. Macrophage activity, as measured by lipopolysaccharide responsiveness, and dendritic cell function, as measured by nominal and alloantigen presentation, were not suppressed in tumor-bearing mice. Therefore, the presence of primary tumor suppresses T-cell and antibody responses; however, surgical removal of primary tumor restores immunocompetence even when disseminated metastatic disease is present.