Tumorantigen

Tumour antigens are antigens ( antibody Generating Sheet ) that are produced by cancer cells and are capable of eliciting an immune response in the affected organism. This feature makes the tumor antigens to important targets in cancer immunotherapy and as tumor markers in the diagnosis.

Origin and Occurrence

The tumor antigens arise as a result of a change in cancer cell genome, or by an altered gene expression ( " on and off " of genes). These changes, new exogenous gene products may arise or proteins that are normally present, for example only in the embryonic stage of development. Existing at the time of disease in healthy cells of the body - - proteins produced in large quantities ( over-expressed ) are often specific.

All these properties and mechanisms leading to differences between normal cells and cancer cells, but not often result in the last two examples in an immune response, since it is not to exogenous gene products.

The tumor antigens should be free in the extracellular space in the cytoplasm or on the cell membrane or by Done antigen shedding. They are divided into two groups: the tumor-specific antigens ( TSA) ( = "new" neo) also referred to as neo-antigens and tumor- associated antigens (TAA). This classification is somewhat idealized, as some " tumor-specific " antigens were later also found in certain normal cells.

Nearly all known tumor antigens are presented on the MHC - I complex to the cell membrane.

Free tumor antigens which are released by antigen shedding into the extracellular space and then circulate in the blood, for example, are used in the diagnosis often as a tumor marker.

Tumor-specific antigens (TSA)

Mutations in the chromosome of tumor cells can lead to novel, unknown to the body, the gene products produced by the cancer cell. These antigens are called tumor- specific since they are only produced by tumors and none else other healthy cell in the body. These gene products ( proteins) present on the cell membrane via the major histocompatibility complex of the outside world of the cell, the respective cancer cell can be recognized by the immune system as "foreign" and eliminated. The cause of the mutations may be, for example, splice variants, point mutations, chromosomal rearrangements or infiltrated by viruses oncogenes.

Since tumor-specific antigens in the normal tissues are not present, TSA -specific T lymphocytes are not negatively selected against in the thymus. The tumor-specific antigens are, however, often expressed only in small numbers of tumor cells and not presented sufficient to compete with normal membrane proteins.

In almost all patients who suffer from a chronic myeloid leukemia, it is in the cancer cells to a reciprocal translocation of chromosomes 9 and 22 in the region of the genes ABL (chromosome 9 locus q34 ) come and BCR (chromosome 22 locus q11 ). The translocation results in the formation of two fusion genes BCR-ABL ( chromosome 22) and BCR - ABL ( chromosome 9). The corresponding gene products are only expressed on the cancer cells and can be recognized as "foreign" by the immune system.

The gene encoding p53 TP53 gene is mutated in many tumors. Accordingly, p53 then modified protein sequences - that is tumor-specific antigens - which are not found in normal cells.

Tumor-associated antigens ( TAA)

While tumor specific antigens are novel alien proteins are produced by cancer cells only, is in the tumor-associated antigens to gene products which are expressed by normal cells. In contrast to the healthy cells, the tumor-associated antigens are over-expressed in cancer cells and presented on the major histocompatibility complex corresponding to frequently on the cell membrane. Since it is normal ubiquitous proteins, an immune response is not often. If the antigen density on the cell membrane is high enough, however, the cancer cells can be recognized and destroyed by specific T cells.

Tyrosinase is an enzyme which is expressed by normal melanocytes. In malignant melanocytes, it is highly overexpressed. Thereby it is possible that patients can form with a malignant melanoma T cells that are specific for tyrosinase. In patients with breast cancer or pancreatic tumor in the tumor tissue, autologous lymphocytes were detected that reacted specifically against the overexpressed by these tumors mucin -1.

Types of tumor antigen

Regardless of the idealized classification into tumor- specific and tumor- associated tumor antigens are classified depending on their expression patterns in different groups:

Differentiation antigens

Differentiation antigens specific to the tissue from which the tumors arise. They are expressed, for example, in malignant melanoma of normal melanocytes. Examples of differentiation antigens tyrosinase and GP100.

Overexpressed antigens

An increased gene expression, tumor cell proteins - which are also produced by normal cells - produce amplified ( overexpress ). Also, post-translational modifications may play a role. Examples of over-expressed tumor antigens hTERT ( a subunit of the enzyme, telomerase ), and mucin -1.

Tumor -testis antigens

The so-called tumor -testis antigens ( engl. cancer / testis antigen ) are found only on cancer cells and healthy tissue only in spermatocytes and in the placenta. These tumor antigens are caused by the reactivation of silent genes that are not transcribed in normal circumstances. The reason for the reactivation, for example, be a reciprocal translocation, wherein the gene is in the proximity of an active promoter.

Since neither MHC -I is still expressed MHC - II in testicular tissue, these cells are immunpriviligiert and are not attacked in an aligned on these antigens therapy. All genes coding for this group of antigens which are located in humans on the X chromosome.

An example of a tumor -testis antigen NY-ESO- 1, which is expressed by many breast, prostate, ovarian carcinomas. Tumor -testis antigens are expected by some authors to the tumor specific antigens.

Mutation antigens

Mutation antigens, also referred to as strukturalterierte antigens are found only in tumor tissues. There are therefore tumor-specific antigens. They are formed in most cases by point mutations in the corresponding genes. Very often find mutation antigens only in the tumor of a patient, as the mutation can be very individual. One speaks in these cases, therefore, also of individual-specific antigens. An exception to this are antigens in which the mutation is the initiating factor for the formation of cancer. An example of this is the proto-oncogene Ras.

Onkovirale proteins

An independent group of tumor antigens form the onkoviralen proteins. One example is the E7 oncoprotein of human papilloma virus 16

Identification of tumor antigens

The identification of tumor antigens with high immunogenicity is one of the biggest challenges for tumor immunology and the key to successful specific immunizations. A basic idea in the identification of tumor antigens is that their perception is by the immune system is an indicator of its relevance in an anti -tumor response. The earlier tumor antigens have been identified by the analysis of the anti-tumor response in patients substantially. To either the peripheral or the tumorinflitrierenden lymphocytes ( TIL) were analyzed, or analyzed, the humoral immune response.

Meanwhile, the process could establish which are largely automated. The two main methods are SEREX (serological identification of antigens by recombinant expression cloning ) and the reverse immunology. With the win in the Human Genome Project findings and with the help of improved analytical methods, has the reverse established for some years, especially immunology as a powerful high-throughput method for the identification of tumor antigens.

Important tumor antigens

To date, over 2000 different tumor antigens have been identified. The ideal tumor antigen would be a structure that is expressed only on cancer cells, and then in the highest possible number. Such antigen, it is not. Just as different cancers represent a distinct disease images, the antigens are expressed depending on the nature and type of the cancer. The antigen expression may be increased by mutation and selection ( by therapeutic intervention, the immune system and even ) of the cancer cells change significantly in the course of the disease even in a tumor in a patient.

For a number of tumor antigen therapeutic monoclonal antibodies have been developed, or are still in clinical testing.

• HER2/neu is expressed in about 20% of all breast cancers, antibodies: Trastuzumab
• EGFR, in 80% of colon carcinomas expressing antibodies: cetuximab
• VEGF, metastatic colorectal cancer, Antibody Bevacizumab
• CAMPATH 1 antigen, chronic lymphocytic leukemia antibodies: Alemtuzumab
• CD22 antibodies: epratuzumab
• CA -125 ovarian cancer antibodies: Oregovomab
• HLA- DR, acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphomas, antibody: Apolizumab
• Mucin -1, colon cancer, lung cancer, breast cancer antibodies: Cantuzumab, vaccine: Stimuvax
• Carcinoembryonic antigen, colon cancer, pancreatic cancer, breast cancer, antibodies (only diagnostically ): Arcitumomab
• Survivin is expressed by many solid tumors, vaccine: Survivac
• Alpha-1 -fetoprotein, germ cell tumors
• Tyrosinase, malignant melanoma
• PSMA major target antigen for a variety of diagnostic and therapeutic applications

Although most antigens are proteins that show cancer cells even in glycolipids and glycoproteins changes compared with normal cells, the principle targets for the immune system, or therapeutics represent.

History

With MAGEA1 ( melanoma antigen family A, 1), the first tumor antigen by Pierre van der Bruggen and colleagues at the Ludwig Institute for Cancer Research was discovered in Brussels in 1991.