《免疫学》（英文版） Chapter 22 Cancer and the Immune System

506 PARt IV The Immune System in Health and Disease receptors. Expression of the receptor for epidermal growth by mating the bd-2 transgenic mice with myc*transgenic factor, which is encoded by c-erbB, has been shown to be mice. These mice develop leukemia very rapidly amplified in many cancer cells And in breast cancer, increased synthesis of the growth-factor receptor encoded by c-neu has Tumors of the Immune System been linked with a poor prognosis. of the immune system are classified as lymphomas The Induction of Cancer Is a Multiste mias. Lymphomas proliferate as solid tumors within Process hoid tissue such as the bone marrow, lymph nodes, or thymus; they include Hodgkins and non-Hodgkins lym- The development from a normal cell to a cancerous cell is phomas Leukemias tend to proliferate as single cells and are ally a multistep process of clonal evolution driven by a detected by increased cell numbers in the blood or lymph. series of somatic mutations that progressively convert the cell Leukemia can develop in lymphoid or myeloid lineages from normal growth to a precancerous state and finally Historically, the leukemias were classified as acute or cancerous state hronic according to the clinical progression of the disease The presence of myriad chromosomal abnormalities in The acute leukemias appeared suddenly and progressed precancerous and cancerous cells lends support to the role of rapidly, whereas the chronic leukemias were much less ag. multiple mutations in the development of cancer. This has gressive and developed slowly as mild, barely symptomatic been demonstrated in human colon cancer, which progresses diseases. These clinical distinctions apply to untreated leuke- in a series of well-defined morphologic stages(Figure 22-4). mias; with current treatments, the acute leukemias often have lon cancer begins as small, benign tumors called adeno- a good prognosis, and permanent remission can often be mas in the colorectal epithelium. These precancerous tumors achieved. Now the major distinction between acute and grow, gradually becoming increasingly disorganized in their chronic leukemias is the maturity of the cell involved. Acute intracellular organization until they acquire the malignant leukemias tend to arise in less mature cells, whereas chronic phenotype. These well-defined morphologic stages of colon leukemias arise in mature cells. The acute leukemias include cancer have been correlated with a sequence of gene changes acute lymphocytic leukemia (ALL) and acute my involving inactivation or loss of three tumor-suppressor genes leukemia(AML); these diseases can develop at (APC, DCC, and p53) and activation of one cellular prolifer- have a rapid onset. The chronic leukemia ation oncogene(K-ras lymphocytic leukemia(CLL) and chronic myelogenous Studies with transgenic mice also support the role of multi- leukemia( CML); these diseases develop slowly and are seen in ple steps in the induction of cancer. Transgenic mice express- adults. ing high levels of Bcl-2 develop a population of small resting A number of B-and T-cell leukemias and lymphomas in B cells, derived from secondary lymphoid follicles, that have volve a proto-oncogene that has been translocated into the greatly extended life spans. Gradually these transgenic mice immunoglobulin genes or T-cell receptor genes. One of the develop lymphomas. Analysis of lymphomas from these mice best characterized is the translocation of c-myc in Burkitt has shown that approximately half have a c-myc translocation lymphoma and in mouse plasmacytomas. In 75% of Burkitt's to the immunoglobulin H-chain locus. The synergism of Myc lymphoma patients, c-myc is translocated from chromosome 8 and Bcl-2 is highlighted in double-transgenic mice produced to the Ig heavy-chain gene cluster on chromosome 14(see Chromosomal 7p eration Loss hypomethylation alterations epithelium epithelium FIGURE 22-4 Model of sequential genetic alterations leading to quence of genetic alterations. Adapted from B. Vogelstein and K. W. metastatic colon cancer. Each of the stages indicated at the bottom is Kinzler, 1993, Trends Genet. 9: 138 morphologically distinct, allowing researchers to determine the se

receptors. Expression of the receptor for epidermal growth factor, which is encoded by c-erbB, has been shown to be amplified in many cancer cells. And in breast cancer, increased synthesis of the growth-factor receptor encoded by c-neu has been linked with a poor prognosis. The Induction of Cancer Is a Multistep Process The development from a normal cell to a cancerous cell is usually a multistep process of clonal evolution driven by a series of somatic mutations that progressively convert the cell from normal growth to a precancerous state and finally a cancerous state. The presence of myriad chromosomal abnormalities in precancerous and cancerous cells lends support to the role of multiple mutations in the development of cancer. This has been demonstrated in human colon cancer, which progresses in a series of well-defined morphologic stages (Figure 22-4). Colon cancer begins as small, benign tumors called adeno￾mas in the colorectal epithelium. These precancerous tumors grow, gradually becoming increasingly disorganized in their intracellular organization until they acquire the malignant phenotype. These well-defined morphologic stages of colon cancer have been correlated with a sequence of gene changes involving inactivation or loss of three tumor-suppressor genes (APC, DCC, and p53) and activation of one cellular prolifer￾ation oncogene (K-ras). Studies with transgenic mice also support the role of multi￾ple steps in the induction of cancer. Transgenic mice express￾ing high levels of Bcl-2 develop a population of small resting B cells, derived from secondary lymphoid follicles, that have greatly extended life spans. Gradually these transgenic mice develop lymphomas. Analysis of lymphomas from these mice has shown that approximately half have a c-myc translocation to the immunoglobulin H-chain locus. The synergism of Myc and Bcl-2 is highlighted in double-transgenic mice produced by mating the bcl-2+ transgenic mice with myc+ transgenic mice. These mice develop leukemia very rapidly. Tumors of the Immune System Tumors of the immune system are classified as lymphomas or leukemias. Lymphomas proliferate as solid tumors within a lymphoid tissue such as the bone marrow, lymph nodes, or thymus; they include Hodgkin’s and non-Hodgkin’s lym￾phomas. Leukemias tend to proliferate as single cells and are detected by increased cell numbers in the blood or lymph. Leukemia can develop in lymphoid or myeloid lineages. Historically, the leukemias were classified as acute or chronic according to the clinical progression of the disease. The acute leukemias appeared suddenly and progressed rapidly, whereas the chronic leukemias were much less ag￾gressive and developed slowly as mild, barely symptomatic diseases. These clinical distinctions apply to untreated leuke￾mias; with current treatments, the acute leukemias often have a good prognosis, and permanent remission can often be achieved. Now the major distinction between acute and chronic leukemias is the maturity of the cell involved. Acute leukemias tend to arise in less mature cells, whereas chronic leukemias arise in mature cells. The acute leukemias include acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML); these diseases can develop at any age and have a rapid onset. The chronic leukemias include chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML); these diseases develop slowly and are seen in adults. A number of B- and T-cell leukemias and lymphomas in￾volve a proto-oncogene that has been translocated into the immunoglobulin genes or T-cell receptor genes. One of the best characterized is the translocation of c-myc in Burkitt’s lymphoma and in mouse plasmacytomas. In 75% of Burkitt’s lymphoma patients, c-myc is translocated from chromosome 8 to the Ig heavy-chain gene cluster on chromosome 14 (see 506 PART IV The Immune System in Health and Disease Chromosomal site Alteration Gene 5q Loss APC 18q Loss DCC 12p Activation K-ras 17p Loss p53 DNA hypomethylation Other alterations Normal epithelium Hyperproliferative epithelium Early adenoma Intermediate adenoma Late adenoma Carcinoma Metastasis FIGURE 22-4 Model of sequential genetic alterations leading to metastatic colon cancer. Each of the stages indicated at the bottom is morphologically distinct, allowing researchers to determine the se￾quence of genetic alterations. [Adapted from B. Vogelstein and K. W. Kinzler, 1993, Trends Genet. 9:138.]

Cancer and the Immune System CHAPTER 22 507 l Promoter Switch region 5●◆Lxm0mm JH Enhancer (a) 5吧y如Mmb增m Enhancer C exons C-lmycexons FIGURE 22-5 In many patients with Burkitt's lymphoma, the c-myc exons(2 and 3)of c-myc are inserted at the S, switch site(b).Only gene is translocated to the immunoglobulin heavy -chain gene cluster exons 2 and 3 of c-myc are coding exons. Translocation may lead to on chromosome 14. In some cases, the entire c-mycgene is inserted overexpression of C-Myc. near the heavy-chain enhancer (a), but in other cases, only the coding Figure 22-3b) In the remaining patients, c-myc remains on (TATAs). Tumor-specific antigens are unique to tumor cells chromosome 8 and the k or y light-chain genes are translo- and do not occur on normal cells in the body. They may cated to a region 3'of c-myc. Kappa-gene translocations result from mutations in tumor cells that generate altered from chromosome 2 to chromosome 8 occur 9% of the time, cellular proteins; cytosolic processing of these proteins and y-gene translocations from chromosome 22 to chromo- would give rise to novel peptides that are presented with class some 8 occur 16% of the time I MHC molecules, inducing a cell-mediated response by Translocations of c-myc to the Ig heavy-chain gene cluster tumor-specific CTLs (Figure 22-6). Tumor-associated anti on chromosome 14 have been analyzed, and, in some cases, gens, which are not unique to tumor cells, may be proteins the entire c-myc gene is translocated head-to-head to a re- that are expressed on normal cells during fetal development gion near the heavy-chain enhancer. In other cases, exons 1, when the immune system is immature and unable to respond 2, and 3 or exons 2 and 3 of c-myc are translocated head-to- but that normally are not expressed in the adult Reactivation head to the Su or Sa switch site( Figure 22-5). In each case, of the embryonic genes that encode these proteins in tumor the translocation removes the myc coding exons from the cells results in their expression on the fully differentiated regulatory mechanisms operating in chromosome 8 and tumor cells. Tumor-associated antigens may also be proteins places them in the immunoglobulin-gene region, a very ac- that are normally expressed at extremely low levels on normal tive region that is expressed constitutively in these cells. The cells but are expressed at much higher levels on tumor cells. It consequences of enhancer-mediated high levels of constitu- is now clear that the tumor antigens recognized by human T sion ive been investigated cells fall into one of four major categories in transgenic mice. In one study, mice containing transgene Antigens encoded by genes exclusively expressed by isting of all three c-myc exons and the immunoglobulin tumors heavy-chain enhancer were produced. Of 15 transgenic pups born, 13 developed lymphomas of the B-cell lineage within a Antigens encoded by variant forms of normal genes that few months of birth have been altered by mutation Antigens normally expressed only at certain stages of Tumor Antigens differentiation or only by certain differentiation lineages a Antigens that are overexpressed in particular tumors The subdiscipline of tumor immunology involves the stud of antigens on tumor cells and the immune response to these Many tumor antigens are cellular proteins that give rise to antigens. Two types of tumor antigens have been identified peptides presented with MHC molecules; typically, these an- on tumor cells: tumor-specific transplantation antigens tigens have been identified by their ability to induce the pro- (TSTAs) and tumor-associated transplantation antigens liferation of antigen-specific CTLs or helper T cells

Figure 22-3b). In the remaining patients, c-myc remains on chromosome 8 and the
or light-chain genes are translo￾cated to a region 3 of c-myc. Kappa-gene translocations from chromosome 2 to chromosome 8 occur 9% of the time, and -gene translocations from chromosome 22 to chromo￾some 8 occur 16% of the time. Translocations of c-myc to the Ig heavy-chain gene cluster on chromosome 14 have been analyzed, and, in some cases, the entire c-myc gene is translocated head-to-head to a re￾gion near the heavy-chain enhancer. In other cases, exons 1, 2, and 3 or exons 2 and 3 of c-myc are translocated head-to￾head to the S or S switch site (Figure 22-5). In each case, the translocation removes the myc coding exons from the regulatory mechanisms operating in chromosome 8 and places them in the immunoglobulin-gene region, a very ac￾tive region that is expressed constitutively in these cells. The consequences of enhancer-mediated high levels of constitu￾tive myc expression in lymphoid cells have been investigated in transgenic mice. In one study, mice containing a transgene consisting of all three c-myc exons and the immunoglobulin heavy-chain enhancer were produced. Of 15 transgenic pups born, 13 developed lymphomas of the B-cell lineage within a few months of birth. Tumor Antigens The subdiscipline of tumor immunology involves the study of antigens on tumor cells and the immune response to these antigens. Two types of tumor antigens have been identified on tumor cells: tumor-specific transplantation antigens (TSTAs) and tumor-associated transplantation antigens (TATAs). Tumor-specific antigens are unique to tumor cells and do not occur on normal cells in the body. They may result from mutations in tumor cells that generate altered cellular proteins; cytosolic processing of these proteins would give rise to novel peptides that are presented with class I MHC molecules, inducing a cell-mediated response by tumor-specific CTLs (Figure 22-6). Tumor-associated anti￾gens, which are not unique to tumor cells, may be proteins that are expressed on normal cells during fetal development when the immune system is immature and unable to respond but that normally are not expressed in the adult. Reactivation of the embryonic genes that encode these proteins in tumor cells results in their expression on the fully differentiated tumor cells. Tumor-associated antigens may also be proteins that are normally expressed at extremely low levels on normal cells but are expressed at much higher levels on tumor cells. It is now clear that the tumor antigens recognized by human T cells fall into one of four major categories: ■ Antigens encoded by genes exclusively expressed by tumors ■ Antigens encoded by variant forms of normal genes that have been altered by mutation ■ Antigens normally expressed only at certain stages of differentiation or only by certain differentiation lineages ■ Antigens that are overexpressed in particular tumors Many tumor antigens are cellular proteins that give rise to peptides presented with MHC molecules; typically, these an￾tigens have been identified by their ability to induce the pro￾liferation of antigen-specific CTLs or helper T cells. Cancer and the Immune System CHAPTER 22 507 5′ JH 3′ Cµ exons Enhancer D Switch region V JH H Promoter Sµ 5′ 3′ Cµ exons Enhancer Sµ 3 2 1 c–myc exons (a) Rearranged Ig heavy–chain gene on chromosome 14 Translocated c–myc gene in some Burkitt's lymphomas 5′ 3′ Cµ exons S 3 2 µ c–myc exons (b) Translocated c–myc gene in other Burkitt's lymphomas L FIGURE 22-5 In many patients with Burkitt’s lymphoma, the c-myc gene is translocated to the immunoglobulin heavy-chain gene cluster on chromosome 14. In some cases, the entire c-myc gene is inserted near the heavy-chain enhancer (a), but in other cases, only the coding exons (2 and 3) of c-myc are inserted at the S switch site (b). Only exons 2 and 3 of c-myc are coding exons. Translocation may lead to overexpression of c-Myc.

508 PARt IV The Immune System in Health and Disease Normal cell Self-peptide Self-peptic Class I mhc Class I MHC Altered se Mutation generates new peptide in class I MHC molecule(TSTa) embryonic gene(TATA) ormal protein (TATA FIGURE 22-6 Different mechanisms generate tumor-specific transplantation antigens(TSTAs) and tumor-associated transplantation antigens(TATAs). The latter are more common. Some Antigens Are Tumor-Specific (tum"), which gives rise to progressively growing tumors, is Tumor-specific antigens have been identified on tumors in- treated in vitro with a chemical cells duced with chemical or physical carcinogens and on some they no longer virally induced tumors. Demonstrating the presence of tumor specific antigens on spontaneously occurring tumors is pal ticularly difficult because the immune response to such tu Immune response to mors eliminates all of the tumor cells bearing sufficient TABLE 22-2 methyl-cholanthrene(MCA) numbers of the antigens and in this way selects for cells bear or polyoma virus(P ing low levels of the antigens. transplanted Live tumor cells Tumor CHEMICALLY OR PHYSICALLY INDUCED lled tumor cells for challenge growth TUMOR ANTIGENS CHEMICALLY INDUCED methylcholanthrene and ultraviolet light are two carcinogens that have been used extensively to generate lines of tumor cells. MCA-induced sarcoma A MCA-induced sarcoma When syngeneic animals are injected with killed cells from a MCA-induced sarcoma A MCA-induced sarcoma carcinogen-induced tumor-cell line, the animals develop a specific immunologic response that can protect against later VIRALLY INDUCED challenge by live cells of the same line but not other tumor-cel lines(Table 22-2). Even when the same chemical carcinogen PV-induced sarcoma A PV-induced sarcoma A duces two separate tumors at different sites in the same ani- PV-induced sarcoma A PV-induced sarcoma B the tumor antigens are distinct and the immune resp PV-induced sarcoma a SV40-induced sarcoma+ to one tumor does not protect against the other tumor. The tumor-specific transplantation antigens of chemically"Tumors were induced either with MCA or PV, and kiled cells from the induced induced tumors have been difficult to characterize because tumors were injected into syngeneic animal, which were then challenged with they cannot be identified by induced antibodies but only by lve cell from the indicated tumor -cell ines. The absence of tumor growth after their T-cell-mediated rejection. One experimental approach Iive challenge indicates tha nmune response induced by tumor antigens that has allowed identification of genes encoding some TSTAs on the killed olls provided protection against the live cells. is outlined in Figure 22-7. When a mouse tumorigenic cell line

Some Antigens Are Tumor-Specific Tumor-specific antigens have been identified on tumors in￾duced with chemical or physical carcinogens and on some virally induced tumors. Demonstrating the presence of tumor￾specific antigens on spontaneously occurring tumors is par￾ticularly difficult because the immune response to such tu￾mors eliminates all of the tumor cells bearing sufficient numbers of the antigens and in this way selects for cells bear￾ing low levels of the antigens. CHEMICALLY OR PHYSICALLY INDUCED TUMOR ANTIGENS Methylcholanthrene and ultraviolet light are two carcinogens that have been used extensively to generate lines of tumor cells. When syngeneic animals are injected with killed cells from a carcinogen-induced tumor-cell line, the animals develop a specific immunologic response that can protect against later challenge by live cells of the same line but not other tumor-cell lines (Table 22-2). Even when the same chemical carcinogen induces two separate tumors at different sites in the same ani￾mal, the tumor antigens are distinct and the immune response to one tumor does not protect against the other tumor. The tumor-specific transplantation antigens of chemically induced tumors have been difficult to characterize because they cannot be identified by induced antibodies but only by their T-cell–mediated rejection. One experimental approach that has allowed identification of genes encoding some TSTAs is outlined in Figure 22-7. When a mouse tumorigenic cell line (tum+ ), which gives rise to progressively growing tumors, is treated in vitro with a chemical mutagen, some cells are mutated so that they no longer are capable of growing into a 508 PART IV The Immune System in Health and Disease Altered self-peptide Mutation generates new peptide in class I MHC molecule (TSTA) Oncofetal peptide Normal cell Inappropriate expression of embryonic gene (TATA) Self-peptide Self-peptide Class I MHC Class I MHC Overexpression of normal protein (TATA) FIGURE 22-6 Different mechanisms generate tumor-specific transplantation antigens (TSTAs) and tumor-associated transplantation antigens (TATAs). The latter are more common. TABLE 22-2 Immune response to methyl-cholanthrene (MCA) or polyoma virus (PV)* Transplanted Live tumor cells Tumor killed tumor cells for challenge growth CHEMICALLY INDUCED MCA-induced sarcoma A MCA-induced sarcoma A – MCA-induced sarcoma A MCA-induced sarcoma B + VIRALLY INDUCED PV-induced sarcoma A PV-induced sarcoma A – PV-induced sarcoma A PV-induced sarcoma B – PV-induced sarcoma A SV40-induced sarcoma C + *Tumors were induced either with MCA or PV, and killed cells from the induced tumors were injected into syngeneic animals, which were then challenged with live cells from the indicated tumor-cell lines. The absence of tumor growth after live challenge indicates that the immune response induced by tumor antigens on the killed cells provided protection against the live cells