The process of malignant transformation can be ascribed to a series of characteristics and definable mutations of genes which encode
proteins that control cell growth and differentiation. During the course of malignant transformation the
cancer-related genes are altered by a variety of mechanisms including translocations, deletions, and point mutations which commonly result in the expression of aberrant
proteins. Our laboratory has focused on determining the extent to which
cancer-specific
proteins expressed by aberrant
cancer-related genes can function as
tumor-specific
antigens. The current paper reviews our studies with two prototype
cancer-specific
proteins, mutated p21ras
protein and chimeric p210bcr-abl
protein. Ras protooncogenes are activated by point mutation in approximately 20% of human
malignancies. The mutations occur primarily at
codons 12 or 61 and result in the expression of p21ras
proteins with single substituted
amino acids. Only a limited number of amino acid substitutions occur. Murine studies demonstrate that immunization with synthetic
peptides corresponding to the mutated segment can elicit both class II restricted CD4+ helper/inducer T-cell responses and class I restricted CD8+ cytotoxic T-cell responses specific for mutated p21ras
protein. In addition, the existence in vivo of
tumors expressing mutated
ras proteins can be detected by assaying for T-cell immunity to the mutated segment of
ras protein. Preliminary human studies show that some patients with
colon cancer have existent antibody responses to p21ras
protein, implying the possible existence of autochthonous T-cell immunity to mutated
ras proteins in those patients. In
chronic myelogenous leukemia the human c-abl protooncogene from chromosome 9 is translocated to the specific breakpoint cluster (bcr) region on chromosome 22. The translocation results in the formation of a bcr-abl fusion gene that encodes at 210-kD chimeric
protein. The joining region segment of chimeric bcr-abl
protein is composed of a unique combination of c-abl and bcr
amino acids and is expressed only by malignant cells. Studies demonstrate that immunization of mice with synthetic
peptides corresponding to the joining region segment can elicit class II restricted CD4+ T-cell responses to p210bcr-abl
proteins. Preliminary studies show that bcr-abl
peptides can bind in the groove of both murine and human class I MHC molecules and can elicit bcr-abl
peptide-specific cytotoxic T lymphocytes (CTL). Whether bcr-abl
peptide-specific CTL can lyse cells expressing bcr-abl
protein is a yet unknown. In summary, the results of the studies reviewed confirm that
cancer-specific oncogenic
proteins can serve as
tumor-specific
antigens.