IMMUNOBIOLOGY OF NEOPLASIA

1 Jun

The experimental and theoretical basis for the field of immunobiology of neoplasia did not be- come reasonably  established  until after 1950, despite studies on tumor transplantation  as dis- cussed below. The observation by Foley in 1953 that mouse neoplasms may be immunogenic for their host as well as a reformulation by Thomas in 1959 of the theory of immune surveillance first proposed by Ehrlich in 1909 formed major aspects of the beginnings of an understanding of the immunobiology of the host-tumor relationship (cf. Brodt, 1983). Although, over the last half century, there has been considerable clinical promise of the utilization of the immunobiology of the host–tumor relationship in the control and therapy of neoplasia (cf. Scott and Cebon, 1997), such promise has never been effectively realized. In fact, some investigators questioned the sig- nificance of any major role that tumor immunology may play in ultimate therapeutic ventures (cf. Chigira et al., 1993). Despite these conflicting ideas and approaches to this problem, there is no question but that the host immune system does interact with malignant neoplasms in a variety of ways. However, as shown further on, in most instances the neoplasm effectively escapes from any definitive resistance of the host to the presence of the neoplasm, despite the fact that neo- plasms clearly express antigens recognized by the host immune system and that definitive re- sponses are produced.

Tumor Antigens

Ever since the early reports by Nowinsky  (1876) and Hanau (1889) of the transplantation  of cancer tissue in dogs and rats, respectively (in contrast to the failure of many others to achieve such results at that time), the antigenicity  of neoplastic cells has been recognized.  Since then numerous examples of tumor transplantation both within individuals and even between species have been reported. In considering the antigenicity of tissue transplantation, certain terms should be defined (Roitt, 1977). An autograft is tissue grafted from one site to another in the same indi- vidual. Isograft designates  transplantation  between syngeneic individuals  (that is, of identical genetic constitution), such as identical twins or animals of the same pure inbred line. Allografts are transplants between allogeneic individuals (that is, members of the same species having dif- ferent genetic constitutions),  for example, transplants  between unrelated humans or from one animal strain to another of the same species. A xenograft is a transplant (graft) between xenoge- neic individuals (that is, of different species), for example, pig to human.

When considering the antigenic structure of neoplasms, the critical question is whether the antigenicity of neoplasms is different in any way from that of their cells of origin. Early investi- gations in this field with inbred mice and hydrocarbon-induced  sarcomas showed that immuno- logical resistance  of the host to the syngeneic  neoplasm  could be established,  although  no immunological  response could be obtained to certain spontaneously  arising neoplasms (Klein and Klein, 1977; Ritts and Neel, 1974). As a result of these studies, Prehn (1973) and Klein (1973), utilizing whole-animal experiments, were able to demonstrate that chemically induced and transplanted neoplasms evoke specific reactions of the cellularly mediated type (T cell) in recipient or host animals. A diagram of the methodology utilized to demonstrate the biological effect of such antigens  is given in Figure 19.19. The antigens  evoking  such reactions  were termed tumor-specific  transplantation  antigens  (TSTA)  and, more recently,  tumor-associated transplantation  antigens (TATA) (cf. Brodt, 1983; Herberman, 1977). For the demonstration  of such antigens, it was important to utilize neoplasms of recent origin, since serial passage through many generations  caused neoplasms  to undergo antigenic changes by mechanisms  not totally understood but quite possibly related to the phenomenon of tumor progression with karyotypic

alterations  (Chapter 8). The TSTAs appeared  to be complex surface antigens,  which are lost upon destruction  of the surface membrane of the cell. Klein (1973) also made the interesting observation that TSTAs of chemically induced neoplasms were essentially unique to each neo- plasm, whereas those of virally induced neoplasms were identical for each virus. Furthermore, it is clear that the TSTAs of virus-induced  cancers are quite distinct from the S and T antigens mentioned earlier in the discussion on viral oncology (Chapter 4). Each neoplasm produced by radiation also appears to have its own unique tumor-specific transplantation antigen. The TSTAs of chemically  or radiation-induced  neoplasms  are in no way related to the specific chemical agent or type of radiation causing the neoplasm, because a single chemical or the same wave- length of radiation can be shown to induce numerous primary neoplasms in one animal, each neoplasm having a different TSTA. Since the original findings of Prehn, Klein, and their associ- ates, there have been reports of chemically induced tumors that do contain common TSTAs (or TATAs) on the basis that immunization  of a host with one neoplasm  led to some protection against challenge by other neoplasms (cf. Herberman, 1977). Some of these findings might be explained by more recent results, as discussed below.

Neoplasms arising spontaneously in animals fail to elicit a specific immunological resis- tance in the transplantation  tests in syngeneic animals (cf. Brodt, 1983). Occasionally  a resis- tance reaction is found, but it is invariably weak, and some investigators argue that, because of this finding, spontaneous  tumors do have TSTAs but that, for practical purposes, they are not sufficiently antigenic to stimulate specific immunologic resistance in the host.

Little is actually known about the chemical nature of TSTAs; however, they may represent the cumulative antigenicity of a number of surface components of the cell, and this allows the host to recognize such a structure as foreign. MHC antigens, while required for the T-cell re- sponse, do not appear to be significant components of the TSTAs, and the expression of “alien antigens” on neoplastic cells does not appear to constitute a significant biological phenomenon (Parham, 1989).

Following the discovery of tumor-specific  transplantation  antigens, T-cell immunity has been recognized as the predominant immune response with the potential to significantly influ- ence the outcome of neoplastic disease and probably other diseases as well (Shu et al., 1997). A number of antigens produced by neoplasms that may induce the T cell responses are listed in Table 19.6. As would be expected, viral gene products that are foreign to the host’s immune system can stimulate T-cell responses, as noted in the table; most T-cell responses to viral gene products would utilize the MHC class I pathway (Figure 19.15). The SV40 T antigen, which occurs primarily in the nucleus, does in fact induce T-cell responses, and there is evidence that T antigen also occurs on the cell surface (Mora, 1982). This finding, together with the evidence for T cell–mediated responses to some of the early gene products of the SV40 virus, has been sug- gested as composing  the TSTA of neoplasms induced by this virus (Dalianis, 1990). Cellular oncogenes, specifically the ras mutant proteins, can induce MHC class II–restricted T cells ca- pable of recognizing  the mutations (Peace et al., 1993). Presumably  this occurs as a result of apoptosis of neoplastic cells bearing the mutated protein, which are then engulfed by antigen-

Figure 19.19 Diagram  of methodology  utilized to determine  the presence  and, by subsequent  experi- ments,  the specificity  of a tumor-specific  transplantation  antigen.  The neoplastic  cells under study are injected into a syngeneic mouse with subsequent  development  of the neoplasm that may metastasize  and kill the animal. Excision of the neoplasm before it has metastasized  (lower left) allows the rejection of a second implant of the same neoplasm, presumably as a consequence of the immunity acquired from expo- sure to the original transplant. (Adapted from Rubin and Farber, 1988, with permission of the authors and publisher.)

presenting cells, and the peptide is presented to T cells. The BCR-ABL fusion cellular oncogene may likewise be induced to cause MHC class II–restricted T cells responsive to specific peptides of the chimeric protein (Chen et al., 1992). Both cellular and humoral immune responses to the mutated (Houbiers et al., 1993) and wild-type (Röpke et al., 1996) p53 gene product have been demonstrated  in mice and humans.  Although  β catenin may be more properly  considered  a proto-oncogene, its association with the APC tumor suppressor gene (Figure 15.2) that regulates its degradation  in association  with other proteins (Kawahara  et al., 2000) may place it in the suppressor  gene category.  Melanomas  have been described  having β catenin mutations  that result in the stabilization of the mutated protein, thus favoring the transcriptional pathway seen in Figure 15.2 (Van den Eynde and van der Bruggen, 1997). Even normal gene products that are overexpressed in neoplastic cells may induce a T cell–mediated response. One of the best exam- ples is the HER-2/neu gene, which codes for an epidermal growth factor–like receptor (see below).

During the last decade, with the realization of the processing of antigens and their presen- tation to T cells, investigations  have attempted to isolate and characterize the peptides of anti- gens on neoplastic cells that are presented to the T-cell antigen receptor. A family of such genes whose products are expressed in a variety of neoplasms is seen in Table 19.7. The gene products recognized  are specific peptides from the entire protein antigen. The only normal tissues ex- pressing these genes appear to be the testis and placenta (cf. Van den Eynde and Boon, 1997). These genes appear to be methylated in most normal cells, and their expression in neoplastic cells may be the result of a genome-wide demethylation seen in neoplastic cells (Chapter 16). A number of differentiation antigens occurring in specific neoplastic cell types as well as their cell of origin have also been found to induce T-cell responses, several of which occur in melanomas but also in other tissues as noted in the table. In fact, several other melanoma  differentiation antigens have been described that induce T cell–mediated responses (cf. Rosenberg, 1996; Van den Eynde and van der Bruggen, 1997). Some of these may be responsible for the relative effi- cacy of immunotherapy with this particular type of neoplasm (see below).

It should be noted that, within the last several years, the methods developed  allow the identification of antigenic peptides presented by MHC class I molecules to tumor-specific cyto- lytic T cells. Both genetic and peptide purification methodologies have been utilized; the reader is referred to specific references for the techniques involved (De Plaen et al., 1997; Cox et al.,1994). With such techniques and others that will undoubtedly be developed in the future, it is becoming increasingly likely that T cell–mediated immunity to specific antigens in specific neo- plasms may be enhanced on a rational basis.

Antigens of Neoplastic Cells Inducing Humoral Responses

Although, as indicated above, the most effective immune response to neoplasms in the host ap- pears to be that of cellular immunity dependent on T-cell responses, a variety of antigens of neo- plasms have been described that either induce the formation of antibodies within the host or can be used as antigens to produce antibodies, usually in xenogeneic hosts, which then may be used as reagents in attempts to kill specific neoplastic  cells in vivo. In Table 19.8 is a listing of a number of antigens associated with neoplastic cells that are reactive with specific antibodies or induce B-cell humoral immune responses. As noted in the table, a number of differentiation an-

Table 19.8 Antigens of Neoplastic Cells That Induce B-Cell Humoral Responses

tigens from the clusters of differentiation (CD) that normally occur on lymphoid cells and other immunocytes may be expressed at high levels in individual neoplasms. Such antigens can induce an antibody response as well as the formation of monoclonal antibodies (Chapter 14). Of the CD antigens seen on the surface of leukemias  and lymphomas,  one that was extensively  studied more than a decade ago, CD10 or the CALLA (common acute lymphoblastic leukemia antigen), is perhaps the best known. This antigen, which actually is a membrane-associated  neutral metal- loendopeptidase  (Shipp et al., 1989), was the target of immunotherapy with specific antibodies (cf. LeBien and McCormack, 1989). Thyroid peroxidase, a major differentiation antigen of thy- roid carcinomas, as noted in Table 19.6, also induces the formation of circulating antibodies in 25% to 50% of patients with thyroid carcinoma  (cf. Baker and Fosso, 1993). Earlier studies (Moore and Hughes, 1973) demonstrated  circulating antibodies to a smooth muscle protein in 45% of patients with sarcomas. Interestingly, about one-third of normal human adult sera tested (Ollert et al., 1996) contain a natural IgM antibody cytotoxic for human neuroblastoma  cells. The antigen appears to be a 260-kDa antigen expressed on neuroblastoma  cells in vivo. This natural humoral immunological host tumor relationship may be associated with the in vivo phe- nomenon of spontaneous neuroblastoma regression (Carlsen, 1990; Evans et al., 1976). The va- riety of glycoproteins  that occur  on the surface7  of cells have also been utilized  for the development of both cell-mediated and antibody responses. We have discussed the carcinoem- bryonic antigen (CEA) gene expression as a marker for gastrointestinal neoplasia (Chapter 17). Another interesting  potential  for immunotherapy  is the fact that many epithelial  cells lining ducts and glands express MUC1, a cell-associated mucin.

In the normal cells this protein is fully glycosylated,  usually on a specific region of the cell as shown in Figure 19.20. In contrast, as briefly discussed in Chapter 16, glycosylation of proteins on neoplastic surfaces many times is incomplete and/or abnormal. This is shown in the figure on the right as a neoplastic cell express- ing MUC1 as well as the MHC class I molecule, but with the MUC1 markedly underglycosy- lated. In this way, components of the protein that are normally not seen by the immune system because of glycosylation now become apparent, and the immune system responds with the for- mation of antibodies as well as cell-mediated  immunity. Also, as briefly discussed in Chapter 16, glycolipids may appear as unique structures on the surface of neoplastic cells because of the abnormalities in the expression of genes coding for enzymes that normally produce the structure of the glycolipid, especially gangliosides  (Lloyd, 1993). Alteration in the structure of mucins may also play other roles in host–tumor relationships  as well as in neoplastic progression (cf. Irimura et al., 1999).

Specific carbohydrate  structures as components  of glycoproteins  on the surface of cells have also been shown to induce antibodies. The Lewis monosaccharide antigens are among these, and just as with the mucoproteins  (Figure 19.20), alterations in the level of enzymes catalyzing the specific formation of terminal carbohydrate structures result in alteration in antigenicity and the potential for such an immune response (Feizi and Childs, 1985). The Her-2/neu protein on mammary and ovarian cancer cells induces not only T cell–mediated immunity (Table 19.6) but also B-cell humoral immunity (Disis and Cheever, 1997). The expression of this gene product is extremely high in the majority of mammary lesions, and thus specific or mono- clonal antibodies are now being used clinically as a therapy for this type of neoplasm (see be- low).  Similarly,  melanoma  antigens  induce  antibodies  within  patients  as well  as those immunized with genetically modified autologous neoplastic cells (Cai and Garen, 1995). A tu- mor-specific  antigen in human glioblastoma  multiforme  as defined by monoclonal  antibodies has also been described (de Tribolet and Carrel, 1980). A series of embryonic neural proteins expressed from the 50 K genes that are highly immunogenic have also been described in small- cell lung cancers in humans which induce B cell-mediated responses in vivo (Güre et al., 2000).

Even circulating antibodies to the p53 protein have frequently been found in the serum of some patients with ovarian carcinoma (Angelopoulou et al., 1996).

In the past, several of the antigens listed in Table 19.8 were considered as tumor-specific antigens (TSA) that were unique to the histogenetic type or class of neoplasm. In the table, this would include thyroid peroxidase and smooth muscle antigen as well as several of the melanoma antigens. While it was felt that these TSAs were relatively unique to the neoplasm expressing such antigens and that primarily humoral responses were evoked by their presence, today this distinction has become less clear, as noted below (Table 19.9).

From this brief discussion of tumor antigens and the responses they induce, it is apparent that neoplastic cells can and do stimulate immune responses within the host. Furthermore,  al- though separated for the sake of convenience,  the reader will note that many antigens induce both T- and B-cell responses, as seen in Table 19.9. It is thus likely that the immune system is quite capable and effective in producing  both T- and B-cell responses  to specific antigens of neoplastic cells. As noted above, apoptosis of neoplastic cells enhances such reactions by the engulfment of internal antigens of neoplastic cells with subsequent processing and presentation through the MHC class II pathway. However, given the considerable antigenicity of neoplastic cells and the effectiveness of the host immune system until the terminal stages of the disease (see below), how is it that the immunobiology  of the host-tumor relationship predominantly  favors the neoplasm?

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