Kleinsmith_immunity_Ch2

Kleinsmith_immunity_Ch2 - Human cancer 1 Extract DNA Apply...

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Unformatted text preview: Human cancer 1 Extract DNA Apply DNA to culture of normal mouse fibroblasts Inject transformed cells into mouse to Confirm capacity of cells to form tumors Figure 2—28 Inducing Cancer by DNA Transfection. When DNA that has been extracted from certain kinds of human cancer cells is introduced into normal mouse cells growing in culture, some of the mouse cells begin to proliferate excessively. When these cells are injected hack into mice, they develop into malignant tumors. TUMOR IMMUNOLOGY The ability of cancer cells to proliferate in an uncontrolled fashion, combined with their capacity to spread through the body, makes them a potentially lethal hazard. Are arty of the body’s normal defense mechanisms capable of protecting against such a threat? The immune system is designed to defend against infection by potentially harmful agents, such as bacteria, viruses, fungi, parasites, and it also attacks foreign tissues and cells. Is the immune system also capable of recognizing cancer cells, and if so, how do cancer cells frequently manage to thrive despite the immune system? in addressing these questions, let us start by reviewing the basic mechanisms involved in an immune response. Immune Responses Are Carried Out by B Lymphocytes, T Lymphocytes, and NK Celts Molecules capable of provoking an immune response are referred to as antigens. To function as an antigen, a sub- stance must be recognized as being “foreign“—that is, different from molecules normally found in a person's body. The more a molecule differs in structure from normal tissue constituents, the greater the intensity of the immune response mounted against that substance. Antigens also need to be susceptible to degradation and processing by cells. This requirement explains why nondegradable foreign materials, such as stainless steel pins and plastic valves, cart be surgically implanted into humans without eliciting an immune response. To trigger an efficient immune response, an antigen must be degraded and processed by specialized antigen-presenting cells that “present” antigens to cells of the immune system in a way designed to activate an immune response. Macrophages and rleitdritir cells are among the most commonly encountered antigen~presenting cells. As shown in Figure 2—2 1 , antigens engulfed by these cells are degraded into small fragments that eventually become bound to cell surface proteins called major histocompatibility complex (MHC) molecules. When an antigen fragment bound to art MHC molecule is present at the surface of an antigen— presenting cell, the MHC—antigen complex stimulates cells called lymphocytes to mount an attack against that partic- ular antigen. The stimulated lymphocytes attack foreign antigens in two different ways. One group of lymphocytes, called B lymphocytes, produce proteins called antibodies, which circulate in the bloodstream and penetrate into extracellular fluids, where they bind to the foreign antigen that induced the itntnune response. Another group of lymphocytes, called cytotoxic T lymphocytes {CTLs}, bind to cells exhibiting foreign antigens on their surface and kill the targeted cells by causing them to burst. in addition to B and T lymphocytes, a small fraction of the total lymphocyte population consists of natural killer ILNK) cells that possess the intrinsic ability to recognize and kill certain kinds of tumor cells (as well as virus—infected cells). In contrast to a typical immune response involving antibody formation or cytotoxic T lymphocytes, NK cells do not need to recognize a specific antigen before attacking a target cell. Instead, they are programmed to attack a broad spectrum of abnormal cells in a relatively indiscrim- inate fashion, while leaving normal cells unharmed. Some Cancer Cells Possess Antigens That Trigger an Immune Response Because so many people develop cancer, it is clear that the ability of NK cells to attack tumors is often overwhelmed. A more powerful and efficient immune response requires Tumor Immunology 37 =__....a .. Hu}.i=-l i 4;—-"‘ £— __ o i’u‘ticien is taken up by Antigen (from cancer cell] / Plasma membrane ,/ ../ ../ ,/ / , / It I MHC Mfg cetl Figure 2—21 an efficient immune response, it must be processed and presented to lymphocytes of the immune system by antigcn-presenling cells such as macrophages and dendritic cells. ll‘tltt‘ antigen is derived from a cancer cell, the cytotoxic T lymphocytes activated in step =3 will selectively attack cancer cells containing that antigen. the participation of Cytotoxic T lymphocytes, whose killing activity is selectively directed at cells containing a specific antigen. For cytotoxic T lymphocytes to become involved, however, they need to recognize an antigen as being foreign or abnormal. The question of whether cancer cells exhibit unique antigens that can elicit such an immune response has had a long and controversial history. Part of the difficulty in reaching a consensus arises because cancers exhibit a variety of antigenic changes. In human melanomas, for example, at least three classes of antigens have been detected. Antigens of the first type are specific both for melanomas and for the person from whom a particular melanoma is obtained. Antigens of the second type are specific for melanomas bttt not for the particular person who has the melanoma. Antigens of the two preceding types cannot be detected in normal cells and are therefore examples of rumor—specific antigens. Antigens of the third type are present in both normal and melanoma Cells, although their concentration in melanoma cells is greater. Such antigens, which are present in higher concentration in a tumor but are not unique to tumors, are more accu- rately referred to as tum{Jr—associated antigens. The distinction between tumor—specific and tuinor~ associated antigens is sometimes difficult to make. For example, a group of molecules called MACE mitig’its are expressed in melanomas and several other cancers but not in most normal tissues. The MAGE antigens are therefore close to being“tumor-specific,” and an itnmune response directed against them would be expected to be reasonably selective, 38 Chapter 2 Profile of a Cancer Cell all‘ .ilffit Antigen Processing by Antigen-Presenting Cells. |'."i [if-.‘s't'P-‘tllt'aJ t-:'-||. {Illilxt'l‘ -.'.i:J'.‘.'Ii e 'II'l“"il"] '- .:t-'.-.: -.n‘..ill f:.i.;.':'i-"it'.\. Antigen— l presenting /' _. 9 Anti-giro 1’:|-;jilll."'ll'\. .1“;- bom‘ti 1t) Vii-it. molt-t llll'\.. alii f.]-'.‘i‘: Milt. tonthL-x -s'.-:.itl‘-et.t--llsL.-'i,1cli'. :9 rte—it lI-if]'1tc‘|‘1IL_)l‘_.-' llti .'-."ii Ill'tJL‘y'll'K :Ill "n.1l.ttt‘-.'|1:Jatt.i: s t ‘.-Jl ill“: d_|]_ Before an antigen can elicit causing minimum damage to normal tissues. Other tumor-associated antigens, such as the prostate-specific antigen (PS/ft} produced by prostate cancer cells, are unique to a specific tissue. Although antigens of this type are produced by normal cells as well, an immune response directed against them would be relatively selective in that it is only directed against a single tissue. Antigens that are genuinely tumor—specific occur in cancers that produce structurally abnormal proteins. Such proteins do not appear in normal cells and thus can be recognized by the immune system as being “foreign.” in Chapters 9 and 10, we will encounter several examples of mutant cancer cell genes that produce abnormal proteins. These molecules can act as antigens that elicit a highly selective, cytotoxic T cell response against the tumor cells in which they are found, provided that the mutant pro— teins are processed and presented to the immune system in the appropriate fashion. The Immune Surveillance Theory Postulates That the Immune System Is Able to Protect Against Cancer The existence of turner-specific antigens raises an inter— esting question: Why don’t people with cancer reject their own tumors? The immune surveillance theory postulates that immune destruction of newly forming cancer cells is in fact a routine event in healthy individuals, and cancer simply reflects the occasional failure of an adequate immune response to be mounted against aberrant cells. The validity of this theory has been debated for many years, with various kinds of evidence being cited both for and against it. Some of the evidence involves organ transplant patients who take intinimosnppressive drugs, which depress immune function and thereby decrease the risk of immune rejection of the transplanted organ. As would be predicted by the immune surveillance theory, individuals treated with immunosuppressive drugs develop many cancers at higher rates than normal (Figure 2—22). Although this finding appears to support the idea that the immune system normally helps prevent cancers from developing, it is also possible that the immunosuppressive drugs are acting directly to trigger the development of cancer. For example. cyclospnrirr—one of the most effective and com- monly used immunosuppressive drugs—has been shown to stimulate the proliferation and motility of isolated cancer cells growing in culture. These results indicate that direct effects of immunosuppressive drugs on newly forming cancer cells may contribute to the increased tumor growth observed in individuals taking such drugs. A more direct approach for evaluating the immune surveillance theory involves the use of animals that ltave been genetically altered to introduce specific defects in the immune system. One study of this type employed mutant mice containing disruptions in RrrgZ, a gene expressed Mouth l Non—Hodgkin‘s lymphoma Kidney '— Thyroid — Cervix _ Bladder Larynx 4—— All sites combined Testis r | Eli Type ofcancer Rectum Colon Lung Prostate Melanoma Breast I 1 1 5 10 Relative cancer rate Figure 2-22 Cancer Rates in Kidney Transplant Patients Taking lmmunusuppressive Drugs. To decrease the risk ofimmune rejection. kidney transplant patients are given immunosuppressive drugs. 'l'hese data show that such individuals develop cancer at higher rates than normal. as would be predicted by the immune surveillance theory. “Relative cancer rate" is the rate for each kind of cancer in individuals taking immunosuppressive drugs divided by the rate in the general population. The dashed line represents :1 value of“ | which would indicate no increase in cancer risk, Il’nased on data from 5. .'\. liirkeland et '.Il., int. i. (Irma-rot! [ W95): I83 t'l'able ll].l only in lymphocytes. The mutant mice. which produce no functional lymphocytes, were found to develop cancer more frequently than do normal mice. An increased cancer risk was observed both for cancers that arise spon— taneously and for cancers that were induced by injecting animals with a cancer-causing chemical. Such results indicate that a norn‘tally functioning itnrnune system helps protect mice against the development of cancer. Nonetheless, the question still exists as to the rele— vance of these findings to human cancers. If the immune system plays a significant role in protecting humans from common cancers, you would expect to see a dramatic increase in overall cancer rates in AIDS patients with severely depressed immune function. While people with AIDS do exhibit higher rates for a few types of cancer, especially Kaposi’s sarcoma and lymphomas, increased rates for the ntore common forms of cancer have ttot been observed. Most ofthe cancers that do occur in higher rates in AIDS patients are known to be caused by viruses (see Figure F-5l. Such observations suggest that immune surveillance may play an important role in protecting humans from virally induced cancers but that it is less effective in preventing the more common forms of cancer. Cancer Cells Have Various Ways of Evading the Immune System Based on the large number of people who develop cancer each year. it is clear that tumors routinely find ways of evading destruction by the immune system. One mecha- nism is based on tumor progression, which refers to the gradual changes in the makeup of cancer cell populations that occur over time as natural selection favors the sur- vival of cells that are more aggressive and aberrant. During tumor progression, cells containing antigens that elicit a strong immune response are most likely to be attacked and destroyed. Conversely, cells that either lack or produce smaller quantities of antigens marking them for destruction are more likely to survive and proliferate. So as tumor progression proceeds, there is a continual selection for cells that invoke less ofan immune response. Cancer cells have also devised ways of actively con— fronting and overcoming the immune system. For example, some cancer cells produce molecules that kill T lymphocytes or disrupt their ability to function. 'l‘umors may also sur— round themselves with a dense layer of supporting tissue that shields them from immune attack. And some cancer cells simply divide so quickly that the immune system cannot destroy them fast enough to keep tumor growth in check. Consequently, the larger a tumor grows, the easier it becomes to overwhelm the immune system. Although tumors are often successful at evading immune attack, immune rejection is not necessarily an unattainable objective. Experiments in mice have shown that immunizing an animal with tumor antigens can trigger an effective immune response under conditions in which the tumor growing in the animal had not elicited any response on its own. Observations like this one suggest Tumor Immunology 39 :_u Eu _ I ._...h'. " Q';_x_ ...
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Kleinsmith_immunity_Ch2 - Human cancer 1 Extract DNA Apply...

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