Homeostasis ^- Eradication Immune escape
FIGURE 2.1 Dual roles of inflammation in immune response and tumor progression. The danger signals derived from tissue damage are able to activate immune effector cells to eradicate tumor cells in cellular homeostasis in the host. During tumor progression, immune effector cells are regulated by anti-inflammatory conditions due to an increase in tumor-derived soluble factors in the tumor microenvironment. Thus, the proinflammatory condition is dominantly shifted to tumor growth through the processes of equilibrium to escape. The balance of proinflammatory and anti-inflammatory conditions to immune effector cells plays a critical role in determining the antitumor immune response to eradicate tumor cells.
expression. Further, two important issues can be suggested: (i) the pfp-mediated cytotoxicity in T cells contributes more to the elimination of lymphoma cells than epithelial tumor cells, whereas IFN-y-mediated cytotoxicity is directed more to the elimination of epithelial tumor cells; (ii) the higher immunogenicity of tumors derived from immunodeficient mice when compared to those from immunocompetent mice indicates less immune selection pressure in the tumors derived from immunodeficient mice than in those of immunocompetent mice. Thus, T cell-mediated elimination has adapted to highly immunogenic tumors, such as chemically and virally induced tumors. On the other hand, the immune selection pressure induces less immuno-genic tumor variants that survive and grow in the tumor microenvironment. In cases of spontaneous tumors appearing for a long period of time, the immunogenic sculpting also produces fewer immunogenic tumors than chemically and virally induced tumors.
Since the equilibrium phase involves the continuous elimination of tumor cells and the production of resistant tumor variants by immune selection pressure, it is likely that equilibrium is the longest of the three processes in cancer immunoediting and may occur over a period of many years. In this process, lymphocytes and IFN-y play a critical role in exerting immune selection pressure on tumor cells. During this period of Darwinian selection, many tumor variants from the original are killed, but new variants emerge carrying different mutations that increase resistance to immune attack. Since the equilibrium model persists for a long time in the interaction between cancer cells and the host, the transmission of cancer during organ transplantation can be considered. One report showed the appearance of metastatic melanoma 1-2 years after transplantation in two patients receiving renal transplants from the same donor. The donor had been previously treated for melanoma 16 years earlier and was considered tumor free (MacKie et al, 2003). Several similar observations have been reported in recipients of allografts from those considered as healthy donors (Cankovic et al, 2006). A possible explanation for the appearance of the transmitted cancer could be that the tumors were kept in equilibrium in the donor, but the continuous administration of immunosuppres-sive drugs activated and facilitated the growth of occult cancer in the recipient.
The final process in cancer immunoedit-ing is the escape phase, which is shown by the outgrowth of tumor cell variants that escaped from immune recognition by effector cells. In this process, tumor variants that acquired insensitivity to immuno-logic detection and subsequent elimination through epigenetic and genetic alterations grew in an uncontrolled manner, resulting in clinically detectable malignant lesions. Surviving tumor variants are able to gain several escape mechanisms for immune surveillance during tumor progression, and the escape mechanisms are categorized by three principles (Malmberg, 2004): (i) lack of tumor antigen (TA) recognition, which is mediated by alterations on tumor cells or effector molecules that are crucial for recognition and activation by the immune system; (ii) lack of susceptibility for cell death, which is mediated by escape from the effector mechanism of cytotoxic lymphocytes; and (iii) induction of immune dysfunction, which is mediated by immu-nosuppressive factors derived from tumor cells and their inducing factors in the tumor microenvironment.
1. Alterations in Signal Transduction Molecules on Effector Cells
Given the lack of TA recognition, which is mediated by alterations of effector molecules that are important for immune system recognition and activation, the loss of signal transducer CD3-Z chain (CD3-Z) of TILs has been attributed to immune evasion in the cooperation of immunosuppressive cyto-kines and local impairment of TILs. The loss of CD3-Z is reported to be correlated with increased levels of IL-10 and TGF-P, and downregulation of IFN-y The CD3-Z chain is located as a large intracytoplasmic homodimer in the TCR that forms a part of the TCR-CD3 complex, which functions as a single transducer upon antigen binding. Since the TCR signal transduction through the formation of CD3 complex is one of three important signals for initiating a successful immune response as well as expressing tumor antigen and T helper 1 (Th1) polarization, any alterations in the CD3-Z chain that are associated with the absence of p56lck tyrosine kinase (but not CD3-Z) produce the changes in the signaling pathway for T cell activation. The alterations of TCR-Z in several types of tumors, such as in pancreatic cancer (Schmielau et al., 2001), uveal malignant melanoma (Staibano et al., 2006), renal cell cancer (Riccobon et al, 2004), ovarian cancer (Lockhart et al., 2001), and oral cancer (Reichert et al, 1998), have been shown to be attributed to immune invasion that links to poor prognosis. Of importance, tumor-derived macrophages or tumor-derived factors led to a selective loss of TCR-Z when compared with CD3-Z (Lockhart et al, 2001). Given that the TCR/CD3-signal-ing led to lymphocyte proliferation, the poor proliferative responses of TILs could be explained by the defect in TCR-Z expression. TIL underwent marked spontaneous apop-tosis in vitro, which was associated with downregulation of the antiapoptotic Bcl-xL and Bcl-2 proteins. Further, since TCR-Z is a substrate of caspase 3 leading to apoptosis, tumor cells can trigger in T lymphocytes caspase-dependent apoptotic cascades, which are not effectively protected by Bcl-2. In oral squamous cell carcinoma, a high proportion of T cells in the tumor undergo apoptosis, which correlates with FasL expression on tumor cells. FasL-positive microvesicles induced caspase-3 cleavage, cytochrome c release, loss of mitochondrial membrane potential, and reduced TCR-Z chain expression in target lymphocytes.
Immunoediting provides a selective pressure in the tumor microenvironment that can lead to malignant progression. A variety of tumor-derived soluble factors, or TDSFs, contribute to the emergence of complex local and regional immunosup-pressive networks, including vascular endothelial growth factor (VEGF), IL-10, TGF-p, prostaglandin E2 (PGE2), soluble phosphatidylserine (sPS), Fas (sFas), FasL (sFasL), and soluble MICA (sMICA) (Kim et al, 2006). Although deposited at the primary tumor site, these secreted factors can extend immunosuppressive effects into local lymph nodes and the spleen, thereby promoting invasion and metastasis.
VEGF plays a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature DCs and macrophages (TiDCs and TAMs). Accumulation of TiDCs may cause roving dendritic cells and T cells to become suppressed through activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors, as discussed in Chapters 19 and 20. VEGF prevents DC differentiation and maturation by suppressing the NF-kB in hematopoietic stem cells. Blocking NF-kB activation in hematopoietic cells by tumor-derived factors is considered to be a mechanism by which tumor cells can directly downregulate the ability of the immune system to generate an antitumor response. In addition, since VEGF can be activated by Stat3, and DC differentiation requires decreasing activity of Stat3, neutralizing antibody specific for VEGF or dominant-negative Stat3 and its inhibitors can prevent Stat3 activation and promote DC differentiation and function. The increased serum levels of VEGF in cancers have been reported to be correlated with poor prognosis, which involves not only angiogenic properties but also the ability to induce immune evasion leading to tumor progression.
Soluble FasL and sMICA products also play important roles in immune evasion by inhibiting Fas- and NKG2D-mediated killing of immune cells. sPS, another TDSF, acts as an inducer of an anti-inflammatory response to TAMs, resulting in the release of anti-inflammatory mediators—such as IL-10, TGF-P, and PGE2—that inhibit immune responses to DCs and T cells. The altered tumor surface antigen, such as FasL, also causes immune evasion by counterattacking immune cells, resulting in cell death. In addition, the soluble forms of FasL and MICA, sFasL and sMICA, are able to inhibit Fas and the NKG2D-mediated death of immune cells. Thus, it is likely that TDSFs play pivotal roles in constituting immuno-suppressive networks that aid tumor progression and metastasis. Indeed, the immunosuppressive networks derived from these TDSFs can be critical factors in causing unsatisfactory clinical responses that are usually seen in immunotherapy of advanced cancer, and they remain an important obstacle to be overcome in the interaction between tumors and the immune system in the tumor microenvironment (Rosenberg et al., 2004; Zou, 2005).
A tumor-specific immune response is regulated by tumor antigen levels and maturation stages of APCs, such as DCs. Many solid tumors, such as sarcomas and carcinomas, express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, the overall immune surveillance against such tumors seems relatively inefficient. Tumor cells are capable of inducing a protective cytotoxic T cell response if transferred as a single-cell suspension. However, if they are transplanted as small tumor pieces, tumors readily grow because the tumor antigen level can be modulated in the tumor microenvironment, which includes not only tumor cells but also bone marrow-derived cells, such as iDCs, and nonbone marrow-derived cells, such as fibroblasts, endothelium, and extracellular matrix (ECM). The ECM binds tumor antigen, and fibroblasts and endo-thelial cells compete with DCs for the antigen. Thus, many tumor antigens are downregulated, thereby facilitating tumor progression. Further, these stromal cells increase interstitial fluid pressure in the tumor, resulting in escape from immune attack by effector cells, as a result of greater difficulties in accessing the tumor. In these situations, insufficient levels of tumor antigen are largely ignored by T cells, adding to the suppressive effects of iDCs in the tumor microenvironment. In addition, iDCs stimulate CD4+CD25 + regulatory T cells, which inhibit T cell activation. It is known that sufficient levels of tumor antigen can produce an immune response, which is mediated by mature DCs presenting tumor antigens to T cells by cross-priming. However, even in the presence of sufficient levels of tumor antigen, iDCs inhibit maturation of DCs and T cell activation, resulting in immunological tolerance.
Thus, it is likely that tumor immune evasion is mediated not only by immuno-logical ignorance due to decreased levels of tumor antigen but also by immunological tolerance due to inhibition of T cell activation by iDCs. Many important events and the central roles of effector cells in the process of immunoediting, from the phases of immune surveillance to escape, are summarized in Figure 2.2.
Clinically detected size
Single transformed cells
Clinically detected size
Stromal remodeling/ angiogenesis Chemokines /receptors
Innate immunity NK/NKT/r ST cells IFN- r /perforin
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