|
|
|
|
Background about Tumor Associated Antigens and Immunogenicity
|
|
Tumor Antigens
Tumor Associated Antigens (TAA) have been the most active genes in the clinical diagnosis and treatment of human carcinoma. TAA are actually normal or mutated genes in the human genome that can elicit humeral or cellular anti-tumor immunity. TAA can be classified into two classes according to their expression pattern, namely tissue restrictive and non tissue restrictive. Tissue restriction means the expression of a gene was restricted to cancer and certain non-vital organs, with very low expression across other human normal tissues.
Tissue restrictive TAA include three well-known types, cancer-testis antigen (CT antigen), differentiation antigen and oncofetal antigen. (CT antigens are TAA expressed restrictively in testis and cancerous tissues, see figure1). Non tissue-restrictive TAA include overexpression antigen and tumor related auto antigen. Tissue restrictive TAA have revolutionized the clinical oncology. For example, PSA as a differentiation antigen has been indispensable in the diagnosis and prognosis evaluation of prostate cancer; AFP as an oncofetal antigen has been active in the diagnosis of hepatocellular carcinoma for many years; NY-ESO-1 as a cancer testis antigen has been put in to the second phase of clinical trial for treatment of hepatocellular carcinoma. Thus identification of clinical applicable TAA has been the central role of cancer immunologists.
Traditionally, TAA are identified through Autologous Typing, T cell epitope Cloning, Serological Typing Techniques, Differential Expression Analyses. Laboratory procedures, although successful, shows to be extremely laborious. With the discovery of more and more novel tumor associated antigens, immunologists found that genes encoding clinically applicable TAA have several shared features in view of transcription: extremely low expression level in vital organs, low expression level in non vital organs, and overexpression in one or more cancer types. Thus successful identification of novel TAA through large-scale expression analysis has been not occasionally reported.
Our lab has been working in this area of insilico cloning for many years. The strategy of identifying tumor specific genes as potential tumor antigen has been shown to be very productive in our own experience. Because of the importance of tumor antigen and the effectivity of insilico cloning, we generate this database to help labs interesting in tumor antigen identification allover the world.
Figure1: An Illustration
of the relationship between tumor antigen subclass and expression
privilege
Immunogenicity
Immunogenicity describes the ability of large molecules to elicit humeral or cellular immunity. The core of immunogenicity was heterogeneity, which means that an immunogen should not be recognized as self-antigen during the negative selection of the T cell repertoire. Tumor specificity actually reflects the heterogeneity with the preclude that the gene do encoding a protein and the protein expression correlates with mRNA expression. That is why we choose tumor specificity penalty as the core of the results.
Different branches of the immune system have different requirements for the protein product to elicit immune reaction. The humeral branch favors stable protein product larger than 10kD, while the cellular branch favors proteins with antigenic peptide, irrespective of the molecular weight of the protein product and its stability in the cell. Thus in order to be a B cell antigen, a gene must encode stable protein larger than 10kD; in order to be T cell antigen, a gene must encode T cell epitope containing protein or peptide.
From the view of anti-tumor effect of the immune response, only B cell antigen with membrane location may produce protective effect, while T cell antigen have no requirement on the subcellular location of the gene product in order to generate protective immunity.
In short, to select genes that hold the potential to the treatment of human carcinoma, genes with higher tumor specificity and higher tissue restriction level, membrane protein larger than 10kD or protein product with multiple predicted T cell epitopes should be favored.
|
|
|
Background
