Tumor antigens of experimental cancers have been historically considered to be antigenically distinct. Early experiments by Prehn and Main (21), Old et al. (22), Globerson and Feldman (15), and Basombrio (16) led to definition of transplantation antigens of methylcholanthrene-induced sarcomas of inbred mice as being antigenically individually distinct, and this became the defining paradigm for cancer immunity. However, recent studies on identification of tumor epitopes recognized by cytotoxic T lymphocytes against human melanomas have begun to challenge this paradigm. So far, at least five cytotoxic T-lymphocytes (CTL)
epitopes have been identified, and in four of these, the CTL epitope is derived from a melanocytic differentiation antigen (23-30). Further, in each case, the amino acid sequence of the melanoma CTL epitope is identical to the corresponding sequence in normal melanocytes. Thus, in contrast to the tumor antigens of mutagenized tumors (31-33), no mutations are detected in CTL epitopes of human melanomas. These results are generating a paradigm shift in our understanding of cancer immunity. It has long been assumed that cancers would contain a repertoire of mutations, some of which will be transforming and some antigenic. The possibility that some of the transforming mutations, for example, those in ras and p53, may themselves be antigenic has also been considered (34-37). The multimutation model of cancers also fits neatly with our understanding of the multistep nature of familial and environmentally induced cancers (38).
These assumptions regarding an inherent mutational repertoire of cancer cells are now being called into question. First, the identified antigenic epitopes are not mutated; hence the idea that cancers are recognized by the immune system because of genetic alterations stands unsubstantiated. Second, immunogenicity of unmutated epitopes raises questions regarding the state of tolerance to self-antigens, particularly differentiation antigens as all known epitopes (with one exception, see refs. 39 and 40) are derived from melanocyte-differentiation antigens. This observation is a reincarnation of one of the earliest speculations on the nature of tumor antigens (41,42) as differentiation antigens. The question of immune response to unaltered antigens also arises with respect to immune response to the HER2/neu oncogene product, which is not altered in tumor cells but is overexpressed in a proportion of breast cancers (43). Finally, and for the purposes of this chapter, most significantly, the presence of unaltered CTL epitopes derived from differentiation antigens suggests that human melanomas possess shared or cross reactive immunogenic antigens. A particular tissue has only a finite set of differentiation antigens, and if genes for these antigens are not mutated in tumor cells, all tumors of a given histological origin can possess only a finite set of immunogenic antigens. Thus, the recent structural studies on CTL epitopes indicate that human melanomas possess shared antigens. Earlier, nonstructural studies have also indicated this cross reactivity (17-19).
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