Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis

• Published in: Blood Vol. 97; no. 1; pp. 192 - 197
• Main Authors: Street, Shayna E.A., Cretney, Erika, Smyth, Mark J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.01.2001; The Americain Society of Hematology
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Cell Transformation, Neoplastic - drug effects; Cytotoxicity Tests, Immunologic; Disease Models, Animal; Fibrosarcoma - chemically induced; Fibrosarcoma - drug therapy; Fibrosarcoma - immunology; Host-tumor relations. Immunology. Biological markers; Interferon-gamma - genetics; Interferon-gamma - pharmacology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Leukocyte Count; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - pharmacology; Methylcholanthrene - pharmacology; Mice; Mice, Inbred Strains; Mice, Knockout; Mice, SCID; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - prevention & control; Neoplasms, Experimental - chemically induced; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - immunology; Perforin; Pore Forming Cytotoxic Proteins; Receptors, Antigen, T-Cell, alpha-beta - immunology; Tumors; Animal model; Carcinoma; Immune response; Cytokine; Rodentia; Cytotoxicity; Natural immunity; Cellular immunity; Malignant tumor; Metastasis; Carcinogenesis; Defense; Natural killer cell; Vertebrata; Mammalia; Mouse; Animal; Dissemination; T-Lymphocyte; Perforin; Tumor cell; Gamma interferon
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V97.1.192

Perforin (pfp) and interferon-γ (IFN-γ) together in C57BL/6 (B6) and BALB/c mouse strains provided optimal protection in 3 separate tumor models controlled by innate immunity. Using experimental (B6, RM-1 prostate carcinoma) and spontaneous (BALB/c, DA3 mammary carcinoma) models of metastatic cancer, mice deficient in both pfp and IFN-γ were significantly less proficient than pfp- or IFN-γ–deficient mice in preventing metastasis of tumor cells to the lung. Pfp and IFN-γ–deficient mice were as susceptible as mice depleted of natural killer (NK) cells in both tumor metastasis models, and IFN-γ appeared to play an early role in protection from metastasis. Previous experiments in a model of fibrosarcoma induced by the chemical carcinogen methylcholanthrene indicated an important role for NK1.1+ T cells. Herein, both pfp and IFN-γ played critical and independent roles in providing the host with protection equivalent to that mediated by NK1.1+ T cells. Further analysis demonstrated that IFN-γ, but not pfp, controlled the growth rate of sarcomas arising in these mice. Thus, this is the first study to demonstrate that host IFN-γ and direct cytotoxicity mediated by cytotoxic lymphocytes expressing pfp independently contribute antitumor effector functions that together control the initiation, growth, and spread of tumors in mice.