T cell-defined human tumor antigens
The discovery of the first human T cell defined-tumor antigen in 1991 by van der Bruggen et al. initiated the discovery of many new tumor antigens. A growing number of these antigens have now been described and close to a dozen of new antigenic peptides are reported in the literature every year. Immunologists now know that human melanoma tumors express antigens that are recognized in vitro by cytolytic T lymphocytes (CTLs) derived from the tumor of the patient. The identified gene was found to direct the expression of antigen MZ2-E on a human melanoma cell line. The antigenic peptide of MZ2-D is a nonapeptide that is encoded by the sequence of MAGE-3 that is homologous to the MAGE-1 sequence coding for the MZ2-E peptide. This gene had no similarity to known sequences and was found to belong to a family of at least three genes. It was found that melanoma cells, other melanoma cell lines, and some tumor cells of other histological types expressed the gene. However, no expression was observed in a panel of normal tissues. Van der Bruggen et al. reported that the antigen MZ2-E appears to be presented by HLA-A1 and that anti-MZ2-E CTLs of the original patient recognized two melanoma cell lines of other HLA-A1 patients that expressed the gene. Furthermore, the researchers speculated that a precisely targeted immunotherapy directed against antigen MZ2-E could be provided to individuals identified by HLA typing and analysis of the RNA of a small tumor sample. Now human tumor antigens recognized by CD4+ or CD8+ T cells are being defined at a regular pace. A database of T cell-defined human tumor antigens has been established.
The data base contains a list of antigens that are grouped into unique antigens and shared antigens. The shared antigens are further divided into tumor-specific antigens, differentiation antigens and over expressed antigens. The tables provide the following information for each antigen:
(a) A GeneCard link for the encoding gene and/or the parent protein,
(b) The HLA presenting molecule and its frequency in Caucasians,
(c) The peptide sequence and its position in the protein sequence,
(d) The method used to isolate the CTL recognizing the antigen,
(e) A PubMed link to the relevant reference.
The database contains a list of “validated peptides” which were selected to meet the following six requirements:
1. Isolation of stable human T lymphocyte clones or lines recognizing the peptide
2. Identification of the peptide recognized by the T cells
3. Identification of the HLA presenting molecule
4. Evidence that the peptide is processed by tumor cells and presented to the specific CTL
What is an antigen?
Let us quickly clarify what an antigen is. An antigen is a rather loosely used term for the target molecules of antibodies or T cells. An antigen, also known as an antibody generator, can be any substance which is able to provoke an adaptive immune response.Often this can be a foreign or toxic substance or an organism, for example, a bacterium, which, once it gets into in a mammalian body, attracts and is bound to a specific antibody. In addition, the origin of the antigen may be within the body, also called a "self" antigen, or from the external environment, called a "non-self" antigen. To describe it more precisely, an antibody binds to a region of an antigen called the epitope. In contrast, the T cell receptor binds to a peptide that is a fragment of the antigen. In addition, the epitope of an antigen is recognized by both, B and T cell receptors.
However, a tumor antigen is a substance produced in tumor cells that can trigger an immune response in the host. Tumor antigens turned out to be useful tumor markers that allow the identification of tumor cells via diagnostic tests. These tumor antigens are now considered as potential candidates for use in cancer therapy. However, normal proteins in the human body are not antigenic since they do not produce an immune response in the host. This phenomenon is called self-tolerance.
Self-tolerance is a process in which self-reacting cytotoxic T lymphocytes (CTLs) and autoantibody-producing B lymphocytes are selected from a large number of self peptides or antigens "centrally" in primary lymphatic tissue (BM) and "peripherally" in secondary lymphatic tissue. This process mostly occurs in the thymus involving T-cells and the spleen or lymph nodes involving B cells. Therefore any protein that is not exposed to the immune system can trigger an immune response. Furthermore, over the years, several preclinical animal studies have convincingly demonstrated that tumor immunity to self antigens can be actively induced and can translate into an effective anti-tumor response.
Tumor Antigens Resulting from Mutations
Shared Tumor-Specific Antigens
Differentiation Antigens
Antigens Overexpressed in Tumors
References
Luigi Buonaguro, Annacarmen Petrizzo, Maria Lina Tornesello and Franco M. Buonaguro; Translating Tumor Antigens into Cancer Vaccines. Clin Vaccine Immunol January 2011 vol. 18 no. 1 23-34.
Novellino L, Castelli C, Parmiani G.; A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother. 2005 Mar;54(3):187-207. Epub 2004 Aug 7.
Roopa Srinivasan and Jedd D Wolchok; Tumor antigens for cancer immunotherapy: therapeutic potential of xenogeneic DNA vaccines.Journal of Translational Medicine 2004, 2:12 doi:10.1186/1479-5876-2-12.
Nathalie Vigneron, Vincent Stroobant, Benoît J. Van den Eynde and Pierre van der Bruggen; Database of T cell-defined human tumor antigens: the 2013 update Cancer Immunity(15 July 2013) Vol. 13, p. 15.
van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T.; A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991 Dec 13; 254 (5038):1643-7.
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