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 cellsFigure 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.