The tumor rejection antigens recognized by the immune system are peptides of tumor-cell proteins that are presented to T cells on MHC molecules. These peptides become the targets of a tumor-specific T-cell response even though they can also be present on normal tissues. For instance, strategies to induce immunity to the relevant antigens in melanoma patients can induce vitiligo, an autoimmune destruction of pigmented cells in healthy skin. Several categories of tumor rejection antigens can be distinguished (Fig. 16.17). One consists strictly of tumor-specific antigens that result from point mutations or gene rearrangements that occur during oncogenesis and that affect a particular gene product. Point mutations in the gene for a particular protein may alter the epitope for T cells by altering the specific residues in a peptide that is already able to bind to MHC class I molecules, or they may allow some mutant peptides to bind de novo to MHC class I molecules. These peptides are often referred to as neoepitopes as they are newly immunogenic versions of normal proteins. Either change may evoke a new T-cell response against the tumor. In Band T-cell tumors, which are derived from single clones of lymphocytes,
The molecules listed here have all been shown to be recognized by cytotoxic T lymphocytes raised from patients with the tumor type listed.
a special class of tumor-specific antigen comprises the unique rearranged antigen receptor expressed by the clone. However, not all mutated peptides may be properly processed or be able to associate with MHC molecules and thus ensure that they stimulate an effective response.
The second category of tumor rejection antigens is the cancer-testis antigens. These are proteins encoded by genes that are normally expressed only in male germ cells in the testis. Male germ cells do not express MHC molecules, and therefore peptides from these molecules are not normally presented to T lymphocytes. Tumor cells show widespread abnormalities of gene expression, including the activation of genes encoding cancer-testis antigens, such as the melanoma-associated antigens (MAGE) (see Fig. 16.17). When expressed by tumor cells, peptides derived from these ‘germ-cell’ proteins can now be presented to T cells by MHC class I molecules. Therefore, these proteins are effectively tumor-specific in their expression as antigens. Perhaps the cancer-testis antigen best characterized immunologically is NY-ESO-1 (New York esophageal squamous cell carcinoma-1), which is highly immunogenic and is expressed by a variety of human tumors, including melanomas.