The most common melanoma antigens are peptides from the enzyme tyrosinase or from three other proteins—gp100, MART1, and gp75. These are differentiation antigens specific to the melanocyte lineage. It is likely that over-expression of these antigens in tumor cells leads to an abnormally high density of specific peptide:MHC complexes and it is this that makes them immunogenic. Although tumor rejection antigens are usually presented as peptides complexed with MHC class I molecules, the enzyme tyrosinase has also been shown to stimulate CD4 T-cell responses in some melanoma patients. This is likely because it is ingested and presented by cells expressing MHC class II molecules. Both CD4 and CD8 T cells are likely to be important in achieving immunological control of tumors. CD8 cells can kill the tumor cells directly, while CD4 T cells have a role in the activation of CD8 cytotoxic T cells and the establishment of memory. CD4 T cells may also kill tumor cells by means of the cytokines that they secrete, such as TNF-α.
Other potential tumor rejection antigens include the products of mutated cellular oncogenes or tumor suppressors, such as Ras and p53, and also fusion proteins, such as the Bcr–Abl tyrosine kinase that results from the chromosomal translocation (t9;22) found in chronic myeloid leukemia (CML). When present on CML cells, the HLA class I molecule HLA-A*0301 can display a peptide derived from the fusion site between Bcr and Abl. This peptide was detected by a powerful technique known as ‘reverse immunogenetics,’ in which endogenous peptides were eluted from the MHC binding groove and their sequence was determined by highly sensitive mass spectrometry.
This technique has identified HLA-bound peptides from other tumor antigens, such as the MART1 and gp100 tumor antigens of melanomas, as well as candidate peptide sequences for vaccination against infectious diseases.
T cells specific for the Bcr–Abl fusion peptide can be identified in peripheral blood from patients with CML by using tetramers of HLA-A*0301 carrying the peptide as specific ligands for the antigen-specific T-cell receptor (see Section 7-24). Cytotoxic T lymphocytes specific for this and other tumor antigens can be selected in vitro by using peptides derived from the mutated or fused portions of these oncogenic proteins; these cytotoxic T cells are able to recognize and kill tumor cells.
After a bone marrow transplant to treat CML, mature lymphocytes from the bone marrow donor infused into the patient can help to eliminate any residual tumor. This technique is known as donor lymphocyte infusion (DLI). At present, it is not clear to what extent the clinical response is due to a graftversus-host effect, in which the donor lymphocytes are responding to general alloantigens expressed on the leukemia cells (see Section 15-36), or whether a specific antileukemic response is important. It is encouraging that it has been possible to separate T lymphocytes in vitro that mediate either a graft-versushost effect or a graft-versus-leukemia effect. The ability to prime the donor cells against leukemia-specific peptides offers the prospect of enhancing the antileukemic effect while minimizing the risk of graft-versus-host disease.
16-16 T cells expressing chimeric antigen receptors are an effective treatment in some leukemias.