Although strong evidence has been presented supporting the existence of a functional cancer immune surveillance process against cancer in mice and humans, cancer continues to develop in intact immune systems and is refractory to many treatment approaches. These findings might be caused by the failure of early host tumor immunity to eradicate nascent transformed cells. Even in the presence of continued immune pressure, the failure to eradicate tumor cells results in tumor progression with reduced immunogenicity. Cancer immunoediting has been proposed in terms of the dual functions of host immunity not only for eliminating tumor cells but also for shaping malignant disease during the period of equilibrium between the tumor and host.
Elimination is the hallmark of the original concept in cancer immune surveillance for the successful eradication of developing tumor cells, working in concert with the intrinsic tumor suppressor mechanisms of the nonimmunogenic surveillance processes. The process of elimination includes innate and adaptive immune responses to tumor cells. For the innate immune response, several effector cells, such as NK, NKT, and y8-T cells, are activated by the inflammatory cytokines that are released by the growing tumor cells, macrophages, and stromal cells surrounding tumor cells. The secreted cytokines recruit more immune cells that produce other proinflam-matory cytokines, such as IL-12 and IFN-y The pfp-, FasL-, and TRAIL-mediated killing of tumor cells by NK cells release tumor antigens (TAs), which lead to adap tive immune responses. In the cross talk between NK cells and DCs, NK cells promote the maturation of DCs and their migration to tumor-draining lymph nodes (TDLNs), resulting in the enhancement of antigen presentation to naive T cells for clonal expansion of CTLs. The TAs-specific T lymphocytes are recruited to the primary tumor site and directly attack and kill tumor cells with the production of cytotoxic INF-y
The following four phases have been proposed for the elimination process (Dunn et al, 2002). The first phase is the recognition of tumor cells by innate immune cells and their limited killing. When a solid tumor has grown to more than 2-3 mm, it requires a blood supply and stromal remodeling for tumor progression, which in turn induces proinflammatory signals leading to the recruitment of innate immune cells that produce IFN-y (e.g., NK, NKT, y8-T cells, macrophages, and DCs) into the tumor site. The transformed cells can be recognized by infiltrating lymphocytes, such as NK, NKT, and y8-T cells, which produce IFN-y. The second phase involves the maturation and migration of DCs and cross-priming for T cells. IFN-y exerts a limited cytotoxicity via antiproliferative and anti-angiogenic effects and induces apoptosis. Some of the chemokines derived from tumors and surrounding nontumorous tissues block the formation of new blood vessels even while continuing to induce tumor cell death. Necrotic tumor cells are ingested by immature DCs (iDCs), which have matured under proinflammatory conditions, and migrate to TDLNs. The third phase is characterized by the generation of TA-specific T cells. The recruited tumor-infiltrating NK and macrophages produce IL-12 and IFN-y, which kill more tumor cells by activating cytotoxic mechanisms, such as pfp, TRAIL, and reactive oxygen. In the TDLNs, the migrated DCs present TAs to native CD4 + T cells that differentiate to CD4 + T cells, which develop TAs-specific CD8+ T cells that lead to clonal expansion. The fourth phase involves the homing of TA-specific T cells to the tumor site and the elimination of tumor cells. Tumor antigen-specific CD4+ and CD8+ T cells home to the primary tumor site, where the CTLs eliminate the remaining TA-expressing tumor cells; this process is enhanced by the secreted IFN-y and also selects for tumor cells with reduced immunogenicity.
The recognition of tumor cells and how the unmanipulated immune system can be activated in a developing tumor, even though tumor-specific antigens may be expressed as distinct recognition molecules on the surface of tumor cells, have been controversial topics in the oncology field. As a hypothesis of the so-called "danger theory," discussed in detail in Chapter 3, it was considered that cellular transformation did not provide sufficient proinflammatory signals to activate the immune system in response to a developing tumor. In the absence of such signals, there is often no immune response, and tolerance may develop. However, studies have indicated that danger signals, such as buildup of uric acid, presence of potential toll-like receptor ligands (e.g., heat shock proteins), the occurrence of a ligand transfer molecule in the signaling cascade induced by CpG DNA, and the presence of extracellular matrix (ECM) derivatives, may induce proinflam-matory responses that activate innate immune responses to foreign pathogens. Danger signals are thought to act by stimulating the maturation of DCs so that they can present foreign antigens and stimulate T lymphocytes. Dying mammalian cells have also been found to release danger signals of unknown identity. Of note, although local limited inflammation may be involved in initiating immune responses, excessive inflammation may promote tumor progression in steady-state conditions. This may be in part due to the anti-inflammatory reactions in APCs, which release anti-inflammatory cytokines such as IL-10 and transforming growth factor
P (TGF-P) that inhibits the activation of effector cells (Figure 2.1).
The equilibrium phase, the next step in cancer immunoediting, is characterized by the continuous sculpting of tumor cells, which produces cells resistant to immune effector cells. This process leads to the immune selection of tumor cells with reduced immunogenicity. These cells are more capable of surviving in an im-munocompetent host, which explains the apparent paradox of tumor formation in immunologically intact individuals. Although random gene mutation may occur in tumors that produce more unstable tumors, these tumor cell variants are less immunogenic, and the immune selection pressure also favors the growth of tumor cell clones with a nonimmmunogenic phe-notype. Several experimental studies using mice with different deficiencies of effector molecules indicated various degrees of immune selection pressure.
Lymphomas formed in pfp-deficient mice were more immunogenic than those in IFN-y-deficient mice, suggesting that pfp may be more strongly involved than IFN-y in the immune selection of lymphoma cells (Street et al, 2002). In contrast, MCA-induced sarcomas in IFN-y receptor-deficient mice are highly immunogenic (Shankaran et al., 2001). Further, chemically induced sarcomas in both nude and SCID mice were more immunogenic than similar tumors from immunocompetent mice (Engel et al, 1997; Smyth et al, 2000a; Shankaran et al., 2001). These findings suggest that the original tumor cells induced in normal mice and selected by a T cellmediated selection process have been adapted to grow in a host with a functional T cell system, which has eliminated highly immunogenic tumor cells, leaving nonim-munogenic tumor cells to grow. There is, however, no connection between this loss of immunogenicity and loss of MHC class I
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