T lymphocytes are cells of the immune system that attack and destroy virus-infected cells, tumor cells and cells from transplanted organs. This occurs because each T cell is endowed with a highly specific receptor that can bind to an antigen present at the surface of another cell. The T cell receptor binds to a complex formed by a surface protein named "MHC" (major histocompatibility complex) and a small peptide of about 9 amino-acids, which is located in a groove of the MHC molecule. This peptide can originate from a protein that remains within the cell (Fig. 1). Whereas each T cell recognizes a single antigen, collectively the T cells are endowed with a large diversity of receptors targeted at a wide variety of antigens. T cells originate in the thymus. There a process named central tolerance eliminates the T cells that have a receptor recognizing an antigen present on normal cells of the organism. This enables the T cells to eliminate cells with "foreign" or "abnormal" antigens without harming the normal cells.
It has long been debated whether cancer cells were bearing "tumor-specific" antigens, absent from normal cells, which could in principle cause the elimination of the tumor by the immune system. It is now proven that tumor-specific antigens exist and that patients mount spontaneous T cell responses against such antigens. Unfortunately, it is clear that in many and perhaps most instances this response is insufficient to prevent cancer progression and metastasis. The purpose of T cell-mediated cancer immunotherapy is to reactivate these responses to a degree that results in tumor destruction without causing harmful effects on normal cells.
Processes leading to the presence of tumor-specific antigens on cancer cells
Gene mutations
As cancer progresses, the genome of cancer cells accumulates point mutations and other genetic abnormalities. Some point mutations result in an amino-acid change in a protein. This can result in the presentation of a new peptide by an MHC molecule. In some instances, the normal sequence does not enable the peptide to bind to a MHC molecule whereas the new peptide does. Hence, a new antigen is present only on the tumor cells. In other instances, the normal peptide is presented at the cell surface and consequently the T lymphocytes that recognize the antigen have been eliminated by the central tolerance process that occurs in the thymus. The mutated peptide is recognized by other T cells which have not been eliminated by central tolerance because it is not presented by normal cells.
Genetic processes other than point mutations can lead to tumor-specific antigens. An interesting example is gene fusions resulting from specific chromosomal translocations frequently encountered in certain types of cancer. The gene fusion produces a chimeric protein segment from which a new antigenic peptide can be derived.
The recognition of mutation-induced antigens on tumors by T cells is only one aspect of a more general phenomenon which can rightly be named: T cell immunosurveillance of the integrity of the genome. Any somatic mutation has a probability of producing a new antigen that can be recognized by T cells. If the mutated cell divides significantly, the resulting clonal population may be eliminated by a T lymphocyte response.
Tumor-specific gene expression
Some genes are expressed by tumor cells and not by normal cells. A class of genes, named cancer-germline genes, is expressed in a large variety of cancer cells but not in normal cells, with the exception of germline cells, which do not carry MHC molecules on their surface and therefore do not present the antigens. Antigenic peptides derived from the encoded proteins are therefore presented on the surface of tumor cells and not on normal cells.
Oncogenic viruses
Some viruses have the ability to transform normal cells into cancer cells. Human oncoviruses include human papilloma virus, Epstein-Barr virus or Kaposi sarcoma-associated virus. The transformed cells often express permanently some viral genes. This leads to the presentation of viral antigenic peptides absent from normal cells.