Antigenic changes on malignant cells

Tumor cells can evade the host's immune response by being poor stimulators of T cells or being poor targets for effector CTL. Because of their genetic instability (24), malignant cells may change in the expression of molecules such as TA, HLA class I antigens as well as APM components, each of which plays a crucial role in the generation of the HLA class I antigen-TA peptide complex (20,21). The latter mediates the recognition of tumor cells by the host's CTL.

3.3.1 TA abnormalities

Abnormalities in TA expression as well as a variable degree of inter- and intra-lesional heterogeneity characterize many tumors. As a result, peptides may not be generated from TA or may be formed in very low amount and the corresponding HLA class I antigen-TA peptide complexes are not formed in spite of the expression of the relevant HLA class I allospecificity. The phenomenon of TA loss has been mainly described in melanoma. Melanocytic differentiation proteins (MDPs, e.g. gp100, MART-1, TRP-1, and tyrosinase) have been found to be lost in metastatic lesions in patients with melanoma independently of the treatment with immunotherapy (120122). More recently, loss of the newly identified melanoma associated antigen, melanoma inhibitor of apoptosis protein (ML-IAP) was reported in a recurred intestinal metastasis in conjunction with a lack of lymphocyte infiltration, following immunotherapy utilizing GM-CSF-secreting autologous tumor cells as immunogens (123). In SCID mice, expansion of MART-1-loss variant of human melanoma cells was causally linked to the presence of adoptively transferred MART-1-specific CD8+ T cells (124). In other types of tumors, e.g., breast cancer, MUC-1 was found to be downregulated in progressive mammary tumors with c-Neu expression in a mouse model (125). Whether the latter finding has a human counterpart remains to be seen. TA mutations which result in a loss of CTL-recognized TA epitopes may also occur in tumors. A mutated TA may still be expressed but the location of the mutation can abolish the generation of epitopes to be recognized by its cognate CTL. The latter is supported by the identification of such a mutation in the p53 protein which inhibits proteasome mediated generation of the p53-derived peptide (p53264-272). This peptide is immunogenic and is known to be recognized by HLA-A*0201-restricted CTL in squamous cell carcinoma of the head and neck (SCCHN) (126). Lastly, tumor cells may present TA-derived peptide analogs with antagonist activity resulting in suboptimal T cell activation (90). These defects due to genetic instability of tumor cells have been found to render malignant cells ineffective targets for TA-specific T cells.

3.3.2 HLA class I antigen abnormalities

A large body of evidence indicates that malignant transformation of cells is associated with changes in classical HLA class I antigen expression (20). As shown in figure 5 these changes range from total loss or downregulation of all HLA class I allospecificities expressed by one cell to selective loss or downregulation of a single HLA class I allospecificity, from loss or downregulation of the gene products of HLA-A, B or C loci to loss of one haplotype, i.e. loss of the HLA class I allospecificities encoded by the genes located in one of the two copies of chromosome #6. The latter carries the major histocompatibility complex in human (127).

The most common types of solid tumors for which more than 100 surgically removed primary lesions have been analyzed include head and neck squamous cell carcinoma (HNSCC), carcinomas of the breast, lung, colon, liver, kidney, cervix and prostate, melanoma, leukemia and lymphoma (20,128-130). For other tumors including stomach (131), pancreatic (132,133), bladder (134,135), ovarian (136,137), germ cell (138) and basal cell (139-141) carcinomas much less information is available regarding HLA class I antigen expression since the number of lesions analyzed is too low for one to draw definitive conclusions. With the exception of liver carcinoma (142-144), leukemia (129) and lymphoma (128,130), the frequency of HLA class I antigen loss and/or downregulation has been found to range between 16% to 80% of the various types of tumors analyzed with mAb recognizing monomorphic determinants. The frequency of this phenotype varies significantly among different malignancies with breast carcinoma and prostate carcinoma demonstrating the highest frequency and RCC and melanoma demonstrating the lowest frequency (20).

While it is clear that abnormalities in classical HLA class I antigen expression do occur in malignant lesions, it should be stressed that the frequency of HLA class I antigen abnormalities reported in the literature for each particular type of malignancy has been found to vary considerably (20).

Figure 5. Defective HLA class I phenotypes identified in malignant cells. The phenotypes identified in tumor cells include total loss and/or downregulation of the gene products of the HLA-A, B and C loci; (a) total loss of all HLA class I antigens encoded in one haplotype; (b) selective downregulation of the gene products of one HLA class I locus; (c) selective loss or downregulation of one HLA class I allospecificity; or complex phenotypes resulting from a combination of two or more of the described phenotypes.

Figure 5. Defective HLA class I phenotypes identified in malignant cells. The phenotypes identified in tumor cells include total loss and/or downregulation of the gene products of the HLA-A, B and C loci; (a) total loss of all HLA class I antigens encoded in one haplotype; (b) selective downregulation of the gene products of one HLA class I locus; (c) selective loss or downregulation of one HLA class I allospecificity; or complex phenotypes resulting from a combination of two or more of the described phenotypes.

Therefore the frequency of HLA class I antigen abnormalities reported in the literature should be interpreted with caution. The reason(s) for differences in the frequency of classical HLA class I antigen defects in various types of tumors is (are) not known. It is likely that these differences partly reflect the sensitivity of the immunohistochemical reaction to detect HLA class I antigens and/or the subjective evaluation of IHC staining. Moreover, there is no information regarding the reproducibility of IHC staining results among different laboratories, although there is some data which demonstrates that variations in the percentage of stained cells enumerated by two experienced observers within the same laboratory is less than 10% (145). Additional sources of variability are represented by differences in the characteristics of the patient population and/or histologic classification of the particular type of tumor analyzed, e.g. ductal vs lobular breast carcinomas with tubular, mucinous, papillary, medullary or adenoid cystic histology, since the role of these variables have not been investigated. In fact, upon review of the literature it is evident that nearly all the studies reported have failed to stratify malignant lesions of a particular tumor according to histologic type. The few studies that have stratified malignant lesions according to histologic type have noted differences in the frequency of HLA class I antigen expression among serous and mucinous-adeno ovarian carcinomas (146) as well as squamous cell, small cell, adeno and large cell lung carcinoma (147). Lastly as we have discussed elsewhere (148), it is our opinion that variable frequency of HLA class I antigen abnormalities observed among tumors of different histotype also reflects the type of immune selective pressure imposed on tumor cell populations, their genetic instability and time length between onset of tumor and diagnosis.

Studies performed mostly with long term culture cell lines derived from surgically removed malignant lesions have identified a number of distinct molecular mechanisms underlying the abnormal HLA class I antigen phenotypes of malignant cells (20). These abnormalities do not represent artifacts of in vitro cell culture, since several of them have also been identified in surgically removed tumors. These mechanisms which are differentially present in different types of tumors include defects in p2-microglobulin (P2m) synthesis, defects in HLA class I heavy chain synthesis, epigenetic alterations involving the HLA class I heavy chain loci, defects in the regulatory mechanisms that control HLA class I antigen expression, abnormalities in one or more of the APM components. This topic has been reviewed by us. We refer the interested reader to our recent papers (20,21).

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