For the immune system to react against a tumor, tumor cells must express antigens that are recognized to be foreign by the individual's immune system. As outlined in Chapter 1, structural alterations of chro mosomes (i.e., aneuploidy) typical of cancerous transformation lead to complex cancer-specific phenotypes, including abnormal cellular and nuclear morphology, metabolism, growth, DNA indices, invasiveness, metastasis, and neoantigens.5,6 Neoantigens are usually subdivided into two major classes:
1. Tumor-specific antigens (TSAs): These substances are unique to cancer cells and cannot be found in their normal counterparts. Shared TSAs found on related tumors from separate individuals include oncoviral antigens expressed on the surfaces of infected cells. Oncogenic viruses found in humans include Epstein-Barr virus (EBV) in Burkitt's lymphoma and nasopharyngeal carcinoma, human T-cell lymphotrophic virus 1 (HTLV-I) in adult T-cell leukemia, human papilloma virus in cervical cancer, hepatitis B virus (HBV) in primary hepatoma, and human herpes virus 8 in Ka-posi sarcoma.
2. Tumor-associated antigens (TAAs): The TAAs can be found in both normal and cancer cells, but their expression is greatly increased in tumors. They include the so-called oncofetal antigens, usually present during embryonic and fetal development, but either absent or present at very low levels in normal adult tissue. The two most important antigens of this group are represented by the carcinoembryonic antigen (CEA) (colon, pancreas, lung, breast, and prostate cancers, cirrhosis of the liver, chronic lung disease, and serum of heavy smokers), and a-fetoprotein (AFP) (liver and testicular cancer).7
The immune system is a complex network of specialized cells and organs that has evolved to defend the body against attacks by foreign invaders. When functioning properly, it fights off infections; when its function is compromised, a number of diseases, ranging from allergy to cancer, may arise.
Two major types of immune response can be distinguished in humans:
1. The humoral immune (HI) response is essentially operated by B lymphocytes through the produc tion of antibodies. Antibodies can kill tumor cells by different mechanisms:
• IgG or IgM antibodies that fix the complement and can destroy soft tumors.
• Antibodies directed against antigens expressed on tumor cell surfaces, which may interfere with the adhesion molecules some tumor cells need to survive
• IgG antibodies, which may mediate tumor cell lysis through antibody dependent cell-mediated cytotoxicity (ADCC), involving effector cells such as macrophages, natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), and perhaps blood neutrophils
2. The cell-mediated immune (CMI) response is operated essentially by macrophages, NK cells, and T lymphocytes. The mechanisms of cancer cell killing vary, in this case, according to the cell type involved, as follows:
• Macrophages, activated by T-cell y-interferon, which kill tumor cells by the same mechanisms they use to kill microorganisms (tumor necrosis factor a, lysozyme, oxygen radicals)
• NK cells, which kill tumors by the same mechanisms they use to kill virus-infected cells (per-forin, granzymes, interferon gamma (IFN-y), FasL-mediated apoptosis)
• Cytotoxic T lymphocytes (CTLs), which kill tumors in an antigen-specific and MHC-restricted manner (perforin, granzymes, IFN-y, FasL-mediated apoptosis)7
As our discussion of the mechanisms of the immune response to cancer will illustrate, CMI, with the intervention of both CTLs (also defined as "killer" cells) and NKs, represents the most efficient mechanism of immune surveillance and immune response to cancer. NK and killer CTL cells represent, therefore, the key players in tumor immunity, being ultimately responsible for the destruction of malignant cells. NKs participate early as the effectors of the innate immune system, and CTLs provide long-lasting effects.8
At the heart of the immune system is its ability to distinguish between antigens that belong to the individual ("self") and those that do not ("non-self"). Virtually every cell of the body carries distinctive molecules that identify it as a self. Molecules that mark a cell as self are encoded by a group of genes that is contained in a section of a specific chromosome and is known as the major histocompatibility complex (MHC). MHC is essential to immune defense because it determines which antigens an individual can respond to and how strongly. Two different classes of MHC are usually recognized:
1. Class I molecules, which alert killer T cells to the presence of body cells that have been changed for the worse (infected with a virus or transformed by cancer) and need to be eliminated 2. Class II molecules, which are found on B cells, macrophages, and other cells responsible for presenting foreign antigen to helper T cells
Regarding the distinction between "self" and "non-self," it must be noted that the innate immune system uses three strategies, which can be described in terms of recognition of "microbial non-self" or "infectious non-self," recognition of "missing self," and recognition of "induced or altered self." The basis of microbial non-self recognition is the ability of the host to recognize products (antigens) that are unique to microorganisms and are not produced by the host. The second strategy relies on the detection of "markers of the normal self." The third strategy, the one of interest for cancer immunology, is based on the detection of "markers of abnormal self" that are induced upon infection (i.e., viral infection) and cellular transformation (cancer). Markers of abnormal self tag the affected cells for elimination by the immune system.9 The concept of self/non-self discrimination has recently evolved toward a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.10
The first line in the immune response to cancer is represented by the natural killer cells, which account for approximately 10 to 20% of peripheral blood lymphocytes and do not express surface antigens typical of both T and B lymphocytes. Unlike CTLs, they do not need to be activated to exert their cytotoxic action. They are primarily restricted to peripheral blood, bone marrow, spleen, and liver and are not found in lymph nodes. NK cells are thought to represent an important defense mechanism against various intracel-lular pathogens, such as herpesvirus, and against certain tumors.
Through specific membrane receptors, NK cells are able to recognize MHC class I molecules [human leukocyte antigen (HLA) class I in humans] on normal cells, leading to the delivery of signals that inhibit their function. As a consequence, NK cells destroy only the target cells that have lost or express insufficient amounts of MHC class I molecules, a frequent event following cancer transformation or viral infec-tion.11
Traditionally, the effectors of the more specific and long-lasting anticancer responses are CTLs. Like NK cells, the CTLs kill tumor cells, but they do it more efficiently and specifically. Also, their intervention requires a network of specific interactions between different cells and molecules. The first element in this network is represented by the so-called antigen presenting cells (APCs), such as macrophages and dendritic cells. APCs are not a single category but rather a group of cells that share the same function, that is, the processing of an antigen and presenting it to the immune system in a form recognizable by T lymphocytes. The processing of an antigen by an APC involves several steps:
1. The APC engulfs the antigen.
2. Enzymes in the APC break down the antigen into smaller fragments.
3. These fragments are transported on the APC's surface and bound to MHC class I molecules.
4. A CTL is now able to recognize the antigen and bind it.
A simplified scheme of the processes involved in the activation of CTLs, which is valid for both virally infected and transformed (cancer) cells, encompasses the following phases:
1. The APC engulfs the antigen.
2. The antigen is processed and associated with MHC class I antigen for recognition.
3. The MHC-associated antigen is recognized by CD8+ lymphocytes.
4. The presence of costimulatory molecules, such as B7-1 and B7-2 on APC and the secretion of inter-leukin 2 (IL-2), promote the differentiation of CD8+ lymphocytes (T cytotoxic) into CTLs;
6. The same processing is simultaneously operating within the MHC class II antigens for recognition by CD4+ lymphocytes (T-helper cells). As a consequence, CD4+ lymphocytes produce lym-phokines that stimulate B lymphocytes to enter the cell cycle and start producing antibodies. No major emphasis, however, is placed on this pathway, given its secondary role in the immune response to tumor (Figure 2.1).
If the proposed mechanisms of immunological response to tumor worked as effectively as described, cancer probably would not exist; unfortunately, this is not the reality. It must therefore be assumed that, for various reasons, the killing of tumor cells by an immunological route is not as effective as described. Among explanations that have been suggested are the following:
1. Most tumor cells are poor APCs because they lack costimulatory molecules (such as B7), and this may determine anergy (lack of response) of T cells to cancer cells.
2. Tumor cells may also lack other molecules (LFA-3 and ICAM-1) required for adhesion of lymphocytes.
3. Some tumor cells show a reduction or complete loss of MHC class I molecules. As reported, this may help recognition by NK cells but, at the same time, it may compromise recognition by CTLs.
Shed ./antigens r
Processed antigen + MHC class II
FIGURE 2.1. Humoral and cell-mediated immunity to cancer.
Processed antigen + MHC class II
FIGURE 2.1. Humoral and cell-mediated immunity to cancer.
4. Molecular complexes made of tumor antigens and specific antibodies (blocking antibodies) can saturate Fc receptors on macrophages, NK cells, neu-trophils, and CTLs, thus preventing the interaction of these cells with the tumor.
5. Tumor surface antigens may be internalized by endocytosis and degraded (antigenic modulation), thus reducing the stimulatory effects of new antigens on the immune system.
6. Some tumors secrete factors (e.g., prostaglandin E2, tumor growth factor ß) that inhibit the development and proliferation of T lymphocytes.
7. Tumors may secrete factors that induce apoptosis in T cells.
More recently, major emphasis has been put on the role of chemokines in both cancer immunotherapy and development. Chemokines are a family of 40 to 50 proteins that regulate leukocyte transport by mediating the adhesion of leukocytes to endothelial cells and the initiation of transendothelial migration and tissue invasion. It has been found that tumors divert chemokines' function to favor tumor development through several mechanisms, including direct growth activity, stimulation of angiogensis, control of spreading and metastatization, and interference with the recruitment of different leukocyte populations. At the same time, it is becoming increasingly evident that through the manipulations of these factors, robust anti-tumor responses can be induced.13'14 Still much
Processed remains to be understood on the manipulation of the immune response.15 This is the ultimate scope of research in the field of cancer immunology, and it is therefore worthwhile to mention some of the major achievements of immunology as applied to the field of clinical cancer research. Immunology can be applied for the detection of tumor antigens (CEA, AFP, etc.) shed in the blood or urine, both in vitro and in vivo, by antibody-based techniques such as ELISA (enzyme-linked immunosorbent assay), radio immune detection (RAID), and immunoscintigraphy. Also, laboratory techniques, such as the mixed lymphocyte-tumor culture (MLTC), test allow the study of the efficiency of cytotoxicity of different cell populations to cancer cells. Finally, immunology has shown a great potential in the field of cancer treatment, allowing the application, with variable but promising results, of new treatment modalities. In this regard, the following are worth mentioning:
1. Anticancer vaccines. The expression of neo-antigens on cancer cell surfaces raises the possibility of using them exactly as bacterial or viral antigens have been used to induce either active or passive immunity to cancer.
2. Therapy with lymphokine-activated killer (LAK) cells. When human peripheral blood mononuclear cells are cultured in vitro with IL-2, they become highly cytotoxic to a wide variety of tumor targets, many of which are resistant to freshly isolated NK cells.
(TILs). This is a variant type of LAK therapy in which the population of killer cells is directly isolated from the tumor. The population of lymphocytes isolated from the tumor and expanded under the influence of IL-2 possesses receptors with high specificity for the tumor, and the final result is a great improvement in the specificity of treatment and reduction of side effects compared with LAK.
4. In vivo cytokine therapy. Some cytokines, such as a-interferon, y-interferon, IL-2, and TGF-a, have been used with some success in cancer treatment.
5. Monoclonal antibodies. A number of treatment modalities exploiting the principle of antigen-antibody reaction have been used with some success in the treatment of cancer and still show great potential. The following three applications deserve mention:
• Chimeric monoclonal antibodies (murine or human antibodies). These substances are much less likely to elicit production of human anti-mouse antibodies than a standard murine monoclonal antibody
• Monoclonal antibodies conjugated with radioisotopes, toxins, or enzymes. In this case, the specificity of the antibody for its particular antigen on the cancer cell surface is exploited to bring drugs or toxins directly into contact with the cancer cell; the result is an overall decrease of the drug dosage and the side effects of treatment;
• Monoclonal heteroconjugates (bispecific monoclonal antibodies). Monoclonal antibodies have been engineered to bind simultaneously to a specific antigen expressed on cancer cell surface and to a specific receptor on either CTLs or NK cells.
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