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

Perforin (pfp) and interferon- (IFN-) together inC57BL/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 andIFN- were significantly less proficient than pfp- or IFN--deficient mice in preventing metastasis of tumor cells to thelung. Pfp and IFN--deficient mice were as susceptible as micedepleted of natural killer (NK) cells in both tumor metastasis models,and IFN- appeared to play an early role in protection frommetastasis. Previous experiments in a model of fibrosarcoma induced bythe chemical carcinogen methylcholanthrene indicated an important rolefor NK1.1⁺ T cells. Herein, both pfp and IFN- playedcritical and independent roles in providing the host with protectionequivalent to that mediated by NK1.1⁺ T cells. Furtheranalysis demonstrated that IFN-, but not pfp, controlled the growthrate of sarcomas arising in these mice. Thus, this is the first studyto demonstrate that host IFN- and direct cytotoxicity mediated bycytotoxic lymphocytes expressing pfp independently contribute antitumoreffector functions that together control the initiation, growth, andspread of tumors in mice.