Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis.
Perforin (pfp) and interferon-gamma (IFN-gamma) 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-gamma were significantly less proficient than pfp- or IFN-gamma-deficient mice in preventing metastasis of tumor cells to the lung. Pfp and IFN-gamma-deficient mice were as susceptible as mice depleted of natural killer (NK) cells in both tumor metastasis models, and IFN-gamma 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-gamma 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-gamma, but not pfp, controlled the growth rate of sarcomas arising in these mice. Thus, this is the first study to demonstrate that host IFN-gamma 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.
Street
S E
SE
Cancer Immunology, Peter MacCallum Cancer Institute, Victoria, Australia.
Cretney
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Smyth
M J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D005354:Fibrosarcoma / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007958:Leukocyte Count; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology*; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000517:prevention & control; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology
D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054353:Perforin; D008748:Methylcholanthrene; D007371:Interferon-gamma