Since it is in the stage of progression that most of our knowledge of the immunobiology of the host–tumor relationship has been gained, it is perhaps not surprising that neoplasms have exhib- ited a variety of methodologies with which to escape the host immune response. As we shall see, it is not unlikely that evolving karyotypic instability, the hallmark of the stage of progression, may be the basis for many of the mechanisms of the failure of the immunobiological host–tumor relation. In a very real sense, as has been so aptly stated, “The tumor fakes out the host.” The variety of modes and mechanisms whereby the neoplasm escapes the host immune response is exemplified in Table 19.10.
Alterations in MHC Expression and Structure in Neoplasia
As briefly discussed above, some workers had reported the occurrence of “alien” MHC mole- cules on the surface of neoplastic cells. While this concept is open for discussion, there are sev- eral concrete examples of altered expression and structure of MHC molecules on neoplastic cells. Mutations within both HLA class I genes (Koopman et al., 1999) as well as class II deter- minants (cf. Möller and Hämmerling, 1992) have been described. In addition, alterations in chromatin structure of the MHC genes in neoplasms of mice have been described (Maschek et al., 1989). A somewhat unique mechanism for neoplastic cells to escape MHC restricted toxicity is the expression of HLA antigens that normally are expressed only on the placenta, specifically HLA-G. This MHC form apparently does not function well in antigen presentation for the re- mainder of the cell types in the organism, but does prevent the action of natural killer (NK) lym- phocytes in effecting the destruction of neoplastic cells that do not express other HLA forms (see below; Paul et al., 1998). In some instances, neoplastic cells express very low levels of MHC class I determinants in amounts that are insufficient to trigger a normal T-cell response (Cohen and Kim, 1994). Furthermore, in experimental situations prostaglandins downregulate the expression of specific MHC antigens in neoplastic cells (Arvind et al., 1995).
Far more common than the few examples given above is the fact that the majority of neo- plasms do not express or downregulate MHC class I and class II antigens. One of the earliest recognitions of this fact was the finding that cells transformed by adenovirus type 12 have a markedly reduced or almost absent expression of MHC class I antigens after infection (Bernards et al., 1983). As a result, such cells were not recognized by the immune system because of the
failure to present antigenic peptides in the MHC molecules to the T-cell receptor. Following this finding, a variety of other viral infections have been shown to produce similar effects by a vari- ety of different mechanisms (cf. Rinaldo, 1994). A sample of the frequency of MHC downregu- lation in human neoplasms may be noted in Table 19.11, which depicts a large number of neoplasms from a variety of different histogenetic origins (Algarra et al., 1997). The loss of ex- pression of MHC antigens is also associated with the natural history of neoplastic development. Marx et al. (1996) demonstrated that the majority of adrenocortical adenomas still express MHC class II antigens, whereas such expression is abrogated in all of the carcinomas of this tissue that were examined. Similarly, metastases from primary melanotic lesions exhibited a greater down- regulation of HLA class I antigen expression, as well as molecules necessary in the pathway of antigen presentation (Kageshita et al., 1999). This loss of MHC antigen expression in the stage of progression is seen diagrammatically in Figure 19.21, as evidenced from immunohistochemi- cal studies of the development of lesions from the stage of promotion to that of progression (Garrido et al., 1993).
Mechanisms of Altered MHC Expression
Because of the considerable complexity of the expression of HLA antigens and their immuno- genic peptides, one might conclude that a variety of different mechanisms will lead to the loss of MHC expression in neoplastic cells. Figure 19.22 presents a brief diagram of potential alter- ations that can lead to the lack of cytotoxic T-cell recognition of antigens presented on the sur- face of neoplastic cells. As noted, alterations in the digestion of the antigen by the proteasome because of the lack of the LMP-2 and LMP-7 subunits of the complex (cf. Figure 19.14) or the elimination of the transporter proteins, TAP-1 and TAP-2 or defects in any of these proteins lead to little or no expression of the MHC antigen with its appropriate immunogenic peptide. Further- more, alterations in the transcription of MHC genes can occur as the result of mutational or ex- cessive expression of protooncogenes including ras (Weijzen et al., 1999), myc (Schrier and Peltenburg, 1993), and NF-kB–binding activity to the promoter region of class I genes (Blanchet et al., 1992). Another mechanism of altered MHC expression is the loss of b2-microglobulin synthesis and expression. As we have previously noted (Figure 19.16), this molecule is an essen- tial component of MHC class I antigens, and in its absence there may be either a lack of expres- sion of the major MHC class I molecule or the expression of the latter may produce an abnormal MHC class I molecule. In either event, the T-cell receptor does not recognize the abnormal pro- tein (cf. Ljunggren, 1992).
Figure 19.21 Diagram of changes seen in the development of cervical carcinoma illustrating alterations in HLA class I expression in normal, preneoplastic, and neoplastic epithelium. Note that the HLA class I losses occur when the “in situ” carcinoma becomes invasive and from this may ultimately produce metastases. Similar patterns have been observed in colon, breast, and laryngeal carcinomas. (Adapted from Garrido et al., 1993, with permission of the authors and publisher.)
Figure 19.22 Diagram of defects in MHC class I-restricted antigen processing in neoplastic cells. The defects noted inclu*de (a) downregulation of LMP2 and LMP7 expression and; (b) downregulation of TAP-1 and TAP-2 and/or alteration in the expression of MHC class I antigen proteins. As noted earlier (Figure 19.14), loss of LMP2 and LMP7 expression blocks the generation of specific peptide epitopes. Loss of TAP-1 and TAP-2 blocks or prevents the transport of peptide epitopes from the cytoplasmic com- partment into the endoplasmic reticulum, where it comes into association with the MHC protein. Any one or all of these defects may result in the lack of expression of MHC molecules carrying appropriate peptide epitopes, thus preventing an interaction with cytotoxic T cells. (Modified from Khanna, 1998, with permis- sion of the author and publisher.)
Perhaps paramount among such alterations is the basic process of the stage of progression, that of evolving karyotypic instability. Such has been argued as the critical mechanism for the alterations in MHC expression seen in neoplastic cells, allowing their evasion from the host im- mune system (Ellem et al., 1998).
Host Tolerance to Antigens of Neoplastic Cells
Any consideration of tolerance of the immune system to specific antigens must take into account the distinction between “self” antigens and “non-self” antigens. In the normal condition, the host immune system is tolerant to self antigens, which consist of MHC antigens with their peptide ligands derived from normal tissues that are available to the immune system during fetal and early neonatal life. Non-self antigens are those originating in the external environment as well as those in immune privileged sites such as the testis or anterior chamber of the eye. These latter sites constitutively express Fas ligand, which interacts with any T cells contacting such tissues, resulting in the death of the interloping T cell (cf. Sotomayor et al., 1996). While the mechanism of the development of tolerance of T cells to self antigens is not entirely clear (Antonia et al.,
1998; Basten, 1998; Sakaguchi, 2000), the immune system of the adult does not normally react to self antigens. As we shall see below, however, the phenomenon of autoimmunity may result from a failure of one or more of the mechanisms of self tolerance, with the resultant production of various disease states.
Since neoplastic cells for the most part express self antigens, the presentation and process- ing of such antigens would not be expected to induce alterations in the immunobiology of the host–tumor relationship. However, tolerance to some fetal antigens such as CEA or α-fetopro-
tein occurs in the host during neonatal life, thus abrogating a T-cell response to such antigens when they are expressed in neoplasms in the adult. Tolerance to specific antigens on neoplastic cells that might be considered non-self by the immune system may also occur by several other mechanisms. Clonal deletion of small numbers of T cells when confronted with an excess of antigen occurs presumably via apoptosis (cf. Starzl and Zinkernagel, 1998). T-cell deletion may also result from reactions with “superantigens,” which may occur on some viruses such as the mouse mammary tumor virus (see below).
Peripheral tolerance of T cells to specific antigens may also occur through the induction of anergy, i.e., the nonresponsiveness of T cells to an antigenic signal. This phenomenon has been reported in several instances when cytotoxic T cells may interact with neoplasms expressing a non-self antigen through the MHC protein but lacking costimulatory molecules needed for the complete interaction of the cytotoxic T cell with the target tumor cell (Kabelitz, 1997). One such family of costimulatory molecules, the B7 family, is upregulated on B cells and antigen-present- ing cells shortly after activation of such cells. These molecules interact with specific receptors, CD28, for members of the B7 family, found on the vast majority of T cells. Neoplastic cells frequently lack such costimulatory molecules and are thus unable to elicit substantial T-cell re- sponses, even when sufficient amounts of relevant MHC molecules are present (Kabelitz, 1997). Thus, the lack of such costimulatory molecules can lead to T-cell anergy, i.e., failure of T-cell response even with appropriate MHC antigens and peptide presentation. In at least one study, the development of antigen-specific T-cell anergy appears to be an early event during tumor pro- gression (Staveley-O’Carroll et al., 1998).
Clonal deletion of T cells as a result of interaction with neoplastic cells may occur by at least two mechanisms. The first, described above, is the formation on the neoplasm of a superan- tigen that is capable of stimulation of T cells but circumventing the requirement for strict MHC restriction. Furthermore, processing of superantigens by the antigen-presenting cell is not re- quired. A diagram of the interaction of a superantigen with the T-cell receptor and MHC com- plex on an antigen-presenting cell is seen in Figure 19.23. Presentation of superantigens requires MHC class II antigens on the presenting cell, but there is less specificity than is seen with usual
Figure 19.23 Schematic representation of the complex between a superantigen, the T-cell receptor, and an MHC class II protein on an antigen-presenting cell. As noted, the superantigen does not present itself within the cleft of the MHC but rather binds to the β chain of the T-cell receptor and components of the MHC class II protein. (Adapted from Herman et al., 1991, with permission of the authors and publisher.)
MHC-restricted responses (cf. Herman et al., 1991). While superantigens activate T cells, they also are capable of eliminating T cells with specific components of the T-cell receptor, particu- larly the β chain (Figure 19.23). Expression of the superantigen on cells with the integrated mouse mammary tumor virus genome resulted in the deletion of specific T-cell clones; this is thought to be critical in the productive infection by the virus and the ultimate formation of ma- lignant neoplasms (Ross, 1997).
Another mechanism for deletion of T-cell clones reactive against specific antigens on neo- plasms is the production of the Fas ligand by the neoplasm. Interaction of such neoplastic cells with T cells can result in the release of the Fas ligand, which interacts with the Fas receptor on the surface of all T cells, leading to their apoptosis (Chapter 17). Increased expression of the Fas ligand on neoplastic cells has been reported with several different neoplasms in both animals and humans (cf. Sotomayor et al., 1996; Shiraki et al., 1997; Strand and Galle, 1998).