Macrophages are innate immunity.
This discovery furthered the development of a previously hypothesized theory, the immunosurveillance theory. The immunosurveillance theory suggests that the immune system routinely patrols the cells of the body, and, upon recognition of a cell, or group of cells, that has become cancerous, it will attempt to destroy them, thus preventing the growth of some tumors. (Burnet, 1970) More recent evidence has suggested that immunosurveillance is only part of a larger role the immune system plays in fighting cancer. Remodeling of this theory has led to the progression of the immunoediting theory, in which there are 3 phases, Elimination, Equilibrium and Escape.
As mentioned, the elimination phase is synonymous with the classic immunosurveillance theory.
In 2001, it was shown that mice deficient in RAG-2 (Recombinase Activator Gene 2) were far less capable of preventing MCA induced tumours then were wild type mice. (Shankaran et al., 2001, Bui and Schreiber, 2007) RAG proteins are necessary for the recombination events necessary to produce TCRs and Igs, and as such RAG-2 deficient mice are incapable of producing functional T, B or NK cells. RAG-2 deficient mice were chosen over other methods of inducting immunodeficiency (such as SCID mice) as an absence of these proteins does not affect DNA repair mechanisms, which becomes important when dealing with cancer, as DNA repair problems can lead to cancers themselves. This experiment provides clear evidence that the immune system does, in fact, play a role in eradication of tumor cells.
Further knock out experiments showed important roles of αβ T cells, γδ T cells and NK cells in tumour immunity (Girardi et al. 2001, Smyth et al., 2001)
Another experiment involving IFN-γ-/- (Interferon γ) showed that these mice are more likely do develop certain types of cancers as well, and suggests a role of CD4+ T cells in tumor immunity, which produce large amounts of IFN-γ (Street et al., 2002)
Perforin deficient mice were also shown to have a reduced ability to ward off MCA induced cancers, suggesting an important role of CD8+ T cells. (Street et al. 2001) Perforin is a protein produced by CD8+ T cells, which plays a central role in the cytotoxic killing mechanisms by providing entry of degradative granzymes into an infected cell. (Abas and Lichtman, 2005)
Finally, the innate immune system has also been associated with immunosurveillance (Dunn et. al, 2004).
The Equilibrium phase of the immunoediting theory is characterized by the continued existence of the tumour, but little growth. Due to the extremely high rate of mutation of cancer cells, it is probable that many will escape the elimination phase, and progress into the equilibrium phase. There is, of yet, little evidence to support the existence of an equilibrium phase, aside from the observation that cancers have been shown to lie dormant, i.e. to go into remission, in a person’s body for years before re-emerging again in the final escape phase. It has been noted that tumors that persist in the equilibrium phase show reduced immunogenicity when compared to tumors which have been grown in immunodeficient mice (Shankaran et al, 2001) Three possible outcomes for tumors managing to evade the immune system, and reach the equilibrium phase have been proposed: 1) eventual elimination by the immune system 2) a prolonged or indefinite period of dormancy, or 3) progression into the final escape phase.
As the name implies, the escape phase is characterized by a reduced immunogenicity of the cancer cells, their subsequent evasion of the immune system and their ability to be clinically detected. A number of theories have been proposed to explain this phase of the theory.
Cancer cells, through mutation, may actually have mutations in some of the proteins involved in antigen presentation, and as such, evade an immune response. (Dunn et al., 2004) Tumor cells may, through mutations, often begin producing large quantities of inhibitory cytokines IL- 10, or Transforming Growth Factor β (TGF-β) (Khong and Restifo, 2002) thereby suppressing the immune system, allowing for large-scale proliferation (Salazar-Onfray et al., 2007). Also, is has been observed that some cancer patients exhibit higher then normal levels of CD4+/CD25+ T cells, a subset of T cells often called regulatory T cells, for their known immunosuppressive actions. These T cells produce high levels of IL-10 and TGF-β, thereby suppressing the immune system and allowing for evasion by the tumor (Shimizu et al., 1999).
Historically, much more attention and funding has been devoted to the role of CD8+ T cells in antitumor immunity, rather than to CD4+ T cells. This can be attributed to a number of things; CD4+ T cells respond only to presentation of antigens by MHC class II, however, most cells express only MHC class I; second, CD8+ T cells, upon being presented with antigen by MHC class I, can directly kill the cancerous cell, through mechanisms which will not be discussed in this article, but which have been well categorized; (See Abbas and Lichtman, 2005) finally, there is simply a more widespread understanding and knowledge of MHC class I tumor antigens, while MHC class II antigens remain somewhat obscure. (Pardol and Toplain, 1998). It was believed that CD4+ T cells were not involved directly in antitumour immunity, but rather functioned simply in the priming of CD8+ T cells, through activation antigen presenting cells (APCs) and increased antigen presentation on MHC class I, as well as secretion of excitatory cytokines such as IL-2 (Pardol and Toplain, 1998, Kalams and Walker, 1998, Wang 2001).
The same series of experiments, examining the role of CD4+ cells, showed that high levels of IL-4 and IFNγ were present at the site of the tumor, following vaccination, and subsequent tumour challenge. (Hung, 1998) IL-4 is the predominant cytokine produced by Th2 cells, while IFNγ is the predominant Th1 cytokine. Earlier work has shown that these two cytokines inhibit the production of each other by inhibiting differentiation down the opposite Th pathway, in normal microbial infections, (Abbas and Lichtman, 2005) yet here they were seen at nearly equal levels. Even more interesting was the fact that both these cytokines were required for maximal tumor immunity, and that mice deficient in either showed greatly reduced antitumor immunity. IFN-γ mice showed virtually no immunity, while IL-4 mice showed a 50% reduction when compared to immunised wildtype mice.
The reduction of immunity in IL-4 deficient mice, has been attributed to a decrease in eosinophil production. In mice deficient in IL-5, the cytokine responsible for differentiation of myeloid progenitor cells into eosinophils, less eosinophils are seen at the site of tumour challenge, which is to be expected. (Hung, 1998) These mice also show reduced antitumor immunity, suggesting that IL-4 defficient mice, which would produce less IL-5, and subsequently have reduced eosinophil levels, elicit their effect through eosinophils.
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