The Revival of Immune Surveillance
Experimental support of immune surveillance began to emerge in the middle 1990s with the development and testing of a variety of mutant mice that were deficient in one or more components of innate or adaptive immune systems. The first evidence came from a series of experimental models that eliminated interferon (IFN)-7, an important cytokine produced mainly by T cells, natural killer (NK) cells, and NKT cells. Mice treated with neutralizing antibodies for IFN-7 and then given transplanted fibrosarcoma tumors exhibited a significant incidence of tumor growth [8]. Kaplan et al. [9] demonstrated that at least one effect of IFN-7 was to directly inhibit tumor growth. They expressed dominant-negative IFN-7 receptors in fibrosarcomas that were then transplanted into recipient mice. Tumors that could not respond to IFN-7 grew significantly faster than tumors with functional IFN-7 receptors. The most convincing evidence for an important role of IFN-7 in protecting the host from developing tumors came from experiments using either IFN-7 gene knockout, or IFN-7 receptor gene knockout mice [9, 10]. Exposure of these knockout mice to the chemical carcinogen methylcholanthrene (MCA) resulted in a 10-to 20-fold increase in tumor formation. In addition, tumors formed more rapidly and grew faster in these knockout mice than in mice with an intact response to IFN-7. Together, the data indicated that: (i) IFN-7 production protected the mice from the induction of chemically induced tumors, and (ii) protection was partly due to a direct inhibitory effect of IFN-7 on tumor growth. Evidence that cytolytic immune effector cells participate in preventing tumor growth was demonstrated in experiments which used perforin gene knockout mice [11]. Perforin is a pore-forming protein released by cytotoxic T cells and NK cells that is essential in lysing the target cell. If perforin knockout mice were treated with MCA, there was a significant increase in tumor incidence compared to tumor incidence in the normal counterparts.
Further evidence that T cells, NKT cells, and B cells protected mice from tumor development was provided by experiments in RAG-1 or RAG-2 gene knockout mice. The RAG gene encodes an enzyme that repairs breaks in double-stranded DNA. Mice that lack the RAG gene are unable to rearrange lymphocyte antigen receptors and therefore, completely lack T cells, NKT cells, and B cells. MCA treatment of these mice also resulted in an increased incidence of tumors [12]. Finally, a role for innate immune effectors was provided by targeted mutations that specifically eliminated either: NKT cells, NK cells, or 78 T cells [13, 14]. These mutant mice all displayed increased sensitivity to MCA-induced tumors.
One of the previous criticisms of the immune surveillance theory was that data supporting a role for immune protection were largely obtained by the induction of tumors with chemical carcinogens, such as MCA. To address this criticism, mice that possess p53 mutations were crossed with the mutant mice described above. Mice with p53 mutations develop a variety of spontaneous tumors [9]. However, if the p53 mutant mice were crossed with either RAG-1, or IFN-7 knockout mice, there was a significant increase in the incidence of spontaneous tumors [15, 16]. These data strongly support a protective role of innate and adaptive immune effector cells in preventing the development of tumors.
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