The role of interferons and other immune components

Encyclopedia of Cancer. Springer-Verlag (2015)

A large body of work provides evidence that both adaptive immunity and innate immunity play a role in controlling the immunogenicity of tumors that develop in the mouse. Most of these studies have focused on the formation of carcinogen-induced sarcomas in mice genetically manipulated to lack the expression of genes required for the generation of lymphocytes and cytokines. Thus in terms of innate immune cells, γδ T cells, natural killer cells, and NKT cells have been shown to be involved in controlling tumor growth as have conventional αβ T cells, the hallmark of the adaptive cellular immune response. The importance of cytotoxic lymphocytes, such as T cells and NK cells, is highlighted by the inability of mice that lack the specific toxic molecules perforin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), expressed by cytotoxic cells, to control both carcinogen-induced and spontaneous tumors. That at least a subset of the lymphocytes that recognize and control tumor growth are MHC class I-restricted, tumor-specific, cytotoxic T cells (CTLs) is evidenced by the fact that mice lacking the LMP2 (low-molecular mass protein 2) proteasome subunit, involved in processing antigen for recognition by CTL, develop spontaneous uterine tumors. The adaptive immune response has evolved to ignore its own tissues, by eliminating self-reactive lymphocytes during their development, in order to avoid autoimmunity or “horror autotoxicus” as Paul Ehrlich termed it. Thus the participation of CTLs in tumor immunoediting implies that tumors must express tumor-associated antigens.

The original observation of immune editing identified a key role for the type II interferon, IFN-γ, in the process. This pleiotropic cytokine is the product of lymphocytes of both the innate (γδ T cells, NK and NKT cells) and adaptive (CD4+ MHC class II-restricted helper T (Th) cells and CD8+ MHC class I-restricted CTLs) immune response. It seems likely that both innate and adaptive lymphocytes are the source of the IFN-γ that shapes the immune response to tumors. The effects of IFN-γ on the immunogenicity of tumors could occur through multiple processes since it is known as a key regulator of adaptive and innate immune responses. There is a great deal of evidence that some of its effects are mediated through host cells in addition to tumor cells. However, given that many tumor cells express IFN-γ receptors, it can directly interact with tumor cells, and there is evidence that it stimulates tumor cells to increase MHC class I expression, downregulate angiogenesis, and promote the infiltration of CTLs into the tumor mass by releasing chemokines. Another cytokine, IL-12, has also been shown to promote tumor immunoediting. IL-12 is intimately involved in the regulation of IFN-γ production early in the immune response and probably mediates its effects through its influence on IFN-γ expression.

In addition to IFN-γ, the type I interferons have a profound influence on tumor growth. Early studies in mice using type I interferons for tumor immunotherapy have been translated into several clinical applications for these cytokines in the therapy of melanoma, CML, follicular lymphoma, hair cell leukemia, and Kaposi sarcoma. There are several important differences in mice and humans between the type II interferon, IFN-γ, which is the sole molecular species, and the type I interferons, IFN-α, for which there are at least 12 variants, and IFN-β, which is unique. Unlike IFN-γ, which is the product only of cells of the lymphocytic lineage, type I interferons can be produced by all nucleated cells when stimulated by products of viral infection and also by infection with some bacteria. As such they are a first line of defense against pathogen invasion of the host. In addition, although tumor cells can express receptors for type I interferons, it appears that unlike IFN-γ, the type I interferons do not act directly on tumor cells and mediate their antitumor effects through host cell responses. Determining exactly which cells are involved requires further study, but they appear to be cells of the hematopoietic lineage. Similar to IFN-γ, there are several points at which type I interferons might influence the immune response to tumors since they can activate dendritic cells, macrophages, and NK cells and are involved in the priming and survival of T cells. In addition, similarly to IFN-γ, they can act on stromal cells within and surrounding tumors to downregulate angiogenic factors. Finally, there is evidence that type I interferons may inhibit the transformation of normal cells by upregulating the expression of the tumor-suppressor molecule, p53. The importance of this class of cytokines in shaping the immune response to tumors was confirmed by studies in mice lacking the IFN-α receptor. Carcinogen-induced sarcomas were found to arise more frequently in these mice and were also shown to be more immunogenic when transplanted into wild-type mice.

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